Prolyl hydroxylase inhibitors

ABSTRACT

The invention described herein relates to certain pyrimidinetrione N-substituted glycine derivatives of formula (I)which are antagonists of HIF prolyl hydroxylases and are useful for treating diseases benefiting from the inhibition of this enzyme, anemia being one example.

CROSS REFERENCE TO PRIOR APPLICATIONS

This application is a Continuation of Ser. No. 16/455,106 filed Jun. 27,2019, which is Allowed; which is a Continuation of Ser. No. 16/023,058filed Jun. 29, 2018, which is now U.S. Pat. No. 10,336,711; which is aContinuation of Ser. No. 15/187,075 filed Jun. 20, 2016, which is nowU.S. Pat. No. 10,035,779; which is a Continuation of Ser. No. 14/791,152filed Jul. 2, 2016 which is Abandoned; which is a Continuation of Ser.No. 14/335,206 filed Jul. 18, 2014 which is Abandoned; which is aContinuation of Ser. No. 14/026,164 filed Sep. 13, 2013 which is nowU.S. Pat. No. 8,815,884; which is a Continuation of Ser. No. 13/667,634filed Nov. 2, 2012 which is now U.S. Pat. No. 8,557,834; which is aContinuation of Ser. No. 12/305,675 filed Jan. 13, 2010 which is nowU.S. Pat. No. 8,324,208; which is a 371 of PCT/US2007/071854 filed Jun.22, 2007 which claims the benefit of Provisional Application No.60/805,602 filed Jun. 23, 2006 which are incorporated herein in theirentirety.

FIELD OF THE INVENTION

This invention relates to certain heteroaromatic N-substituted glycinederivatives that are inhibitors of HIF prolyl hydroxylases, and thushave use in treating diseases benefiting from the inhibition of thisenzyme, anemia being one example.

BACKGROUND OF THE INVENTION

Anemia occurs when there is a decrease or abnormality in red bloodcells, which leads to reduced oxygen levels in the blood. Anemia occursoften in cancer patients, particularly those receiving chemotherapy.Anemia is often seen in the elderly population, patients with renaldisease, and in a wide variety of conditions associated with chronicdisease.

Frequently, the cause of anemia is reduced erythropoietin (Epo)production resulting in prevention of erythropoiesis (maturation of redblood cells). Epo production can be increased by inhibition of prolylhydroxylases that regulate hypoxia inducible factor (HIF).

One strategy to increase erythropoietin (Epo) production is to stabilizeand thus increase the transcriptional activity of the HIF. HIF-alphasubunits (HIF-1alpha, HIF-2alpha, and HIF-3alpha) are rapidly degradedby proteosome under normoxic conditions upon hydroxylation of prolineresidues by prolyl hydroxylases (EGLN1, 2, 3). Proline hydroxylationallows interaction with the von Hippel Lindau (VHL) protein, a componentof an E3 ubiquitin ligase. This leads to ubiquitination of HIF-alpha andsubsequent degradation. Under hypoxic conditions, the inhibitoryactivity of the prolyl hydroxylases is suppressed, HIF-alpha subunitsare therefore stabilized, and HIF-responsive genes, including Epo, aretranscribed. Thus, inhibition of prolyl hydroxylases results inincreased levels of HIF-alpha and thus increased Epo production.

The compounds of this invention provide a means for inhibiting thesehydroxylases, increasing Epo production, and thereby treating anemia.Ischemia, myocardial infarction, stroke, and cytoprotection may alsobenefit by administering these compounds.

SUMMARY OF THE INVENTION

In the first instance, this invention relates to a compound of formula(I):

wherein:

-   -   R¹ and R⁴ are each independently selected from the group        consisting of hydrogen, —NR⁵R⁶, C₁-C₁₀alkyl, C₂-C₁₀alkenyl,        C₂-C₁₀alkynyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkyl-C₁-C₁₀alkyl,        C₅-C₈cycloalkenyl, C₅-C₈cycloalkenyl-C₁-C₁₀alkyl,        C₃-C₈heterocycloalkyl, C₃-C₈heterocycloalkyl-C₁-C₁₀alkyl, aryl,        aryl-C₁-C₁₀alkyl, heteroaryl and heteroaryl-C₁-C₁₀alkyl;    -   R² is —NR⁷R⁸ or —OR⁹;    -   R³ is H or C₁-C₄alkyl;        -   where R⁵ and R⁶ are each independently selected from the            group consisting of hydrogen, C₁-C₁₀alkyl, C₃-C₈cycloalkyl,            C₃-C₈cycloalkyl-C₁-C₁₀alkyl, C₃-C₈heterocycloalkyl,            C₃-C₈heterocycloalkyl-C₁-C₁₀alkyl, aryl, aryl-C₁-C₁₀alkyl,            heteroaryl, heteroaryl-C₁-C₁₀alkyl, —C(O)C₁-C₄alkyl,            —C(O)C₃-C₆cycloalkyl, —C(O)C₃-C₆heterocycloalkyl, —C(O)aryl,            —C(O)heteroaryl and —S(O)₂C₁-C₄alkyl, or, when R⁵ and R⁶ are            attached to the same nitrogen, R⁵ and R⁶ taken together with            the nitrogen to which they are attached form a 5- or 6- or            7-membered saturated ring optionally containing one other            heteroatom selected from oxygen, nitrogen and sulphur,        -   R⁷ and R⁸ are each independently selected from the group            consisting of hydrogen, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl,            C₂-C₁₀alkynyl, C₃-C₈cycloalkyl, C₃-C₈heterocycloalkyl, aryl            and heteroaryl, and        -   R⁹ is H or a cation, or C₁-C₁₀alkyl which is unsubstituted            or substituted with one or more substituents, suitably from            1 to 6 substituents, suitably from 1 to 3 substituents,            independently selected from the group consisting of            C₃-C₆cycloalkyl, heterocycloalkyl, aryl and heteroaryl;    -   X is O or S; and    -   Y is O or S;        -   where any carbon or heteroatom of R¹, R², R³, R⁴, R⁵, R⁶,            R⁷, R⁸, R⁹ is unsubstituted or, where possible, is            substituted with one or more substituents, suitably from 1            to 6 substituents, suitably from 1 to 3 substituents,            independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl,            halogen, —OR¹⁰, —NR⁵R⁶, oxo, cyano, nitro, —C(O)R¹⁰,            —C(O)OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —NR⁵R⁶, —CONR⁵R⁶,            —N(R⁵)C(O)R¹⁰, —N(R⁵)C(O)OR¹⁰, —OC(O)NR⁵R⁶, —N(R⁵)C(O)NR⁵R⁶,            —SO₂NR⁵R⁶, —N(R⁵)SO₂R¹⁰, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl,            C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, aryl,            C₁-C₆alkyl-aryl, heteroaryl and C₁-C₆alkyl-heteroaryl,            wherein R¹ and R⁶ are the same as defined above and R¹⁰ is            selected from hydrogen, C₁-C₁₀alkyl, C₂-C₁₀alkenyl,            C₂-C₁₀alkynyl, —C(O)C₁-C₄alkyl, —C(O)aryl, —C(O)heteroaryl,            —C(O)C₃-C₆cycloalkyl, —C(O)C₃-C₆heterocycloalkyl,            —S(O)₂C₁-C₄alkyl, C₃-C₅cycloalkyl, C₃-C₅heterocycloalkyl,            C₆-C₁₄aryl, aryl-C₁-C₁₀alkyl, heteroaryl and            heteroaryl-C₁-C₁₀alkyl;            and/or a pharmaceutically acceptable salt or solvate            thereof.

In a second aspect of the present invention, there is provided acompound of formula (I) and/or a pharmaceutically acceptable salt orsolvate thereof for use in mammalian therapy, including human therapy,e.g. treating amenia. An example of this therapeutic approach is that ofa method for treating anemia which is effected by increasing theproduction of erythropoietin (Epo) by inhibiting HIF prolyl hydroxylasescomprising administering a compound of formula (I) and/or apharmaceutically acceptable salt or solvate thereof, to a patient inneed thereof, neat or admixed with a pharmaceutically acceptableexcipient or excipients, in an amount sufficient to increase productionof Epo.

In a third aspect of the present invention, there is provided apharmaceutical composition comprising a compound of formula (I), and/ora pharmaceutically acceptable salt or solvate thereof, and one or moreof pharmaceutically acceptable carriers, diluents and excipients.

In a fourth aspect, there is provided the use of a compound of formula(I) and/or a pharmaceutically acceptable salt or solvate thereof, in thepreparation of a medicament for use in the treatment of a disordermediated by inhibiting HIF prolyl hydroxylases, such as an anemia, thatcan be treated by inhibiting HIF prolyl hydroxylases.

In a fifth aspect, there is provided methods of co-administering thepresently invented compounds of formula (I) with further activeingredients.

DETAILED DESCRIPTION OF THE INVENTION

For the avoidance of doubt, unless otherwise indicated, the term“substituted” means substituted by one or more defined groups. In thecase where groups may be selected from a number of alternative groupsthe selected groups may be the same or different.

The term “independently” means that where more than one substituent isselected from a number of possible substituents, those substituents maybe the same or different.

An “effective amount” means that amount of a drug or pharmaceuticalagent that will elicit the biological or medical response of a tissue,system, animal or human that is being sought, for instance, by aresearcher or clinician. Furthermore, the term “therapeuticallyeffective amount” means any amount which, as compared to a correspondingsubject who has not received such amount, results in improved treatment,healing, prevention, or amelioration of a disease, disorder, or sideeffect, or a decrease in the rate of advancement of a disease ordisorder. The term also includes within its scope amounts effective toenhance normal physiological function.

As used herein the term “alkyl” refers to a straight- or branched-chainhydrocarbon radical having the specified number of carbon atoms, so forexample, as used herein, the terms “C₁-C₄alkyl” and “C₁-C₁₀ alkyl”refers to an alkyl group having at least 1 and up to 4 or 10 carbonatoms respectively. Examples of such branched or straight-chained alkylgroups useful in the present invention include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, t-butyl,n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl,and branched analogs of the latter 5 normal alkanes.

When the term “alkenyl” (or “alkenylene”) is used it refers to straightor branched hydrocarbon chains containing the specified number of carbonatoms and at least 1 and up to 5 carbon-carbon double bonds. Examplesinclude ethenyl (or ethenylene) and propenyl (or propenylene).

When the term “alkynyl” (or “alkynylene”) is used it refers to straightor branched hydrocarbon chains containing the specified number of carbonatoms and at least 1 and up to 5 carbon-carbon triple bonds. Examplesinclude ethynyl (or ethynylene) and propynyl (or propynylene).

“Haloalkyl” refers to an alkyl group that is substituted with one ormore halo substituents, suitably from 1 to 6 substituents. Haloalkylincludes trifluoromethyl.

When “cycloalkyl” is used it refers to a non-aromatic, saturated, cyclichydrocarbon ring containing the specified number of carbon atoms. So,for example, the term “C₃-C₈cycloalkyl” refers to a non-aromatic cyclichydrocarbon ring having from three to eight carbon atoms.

Exemplary “C₃-C₈cycloalkyl” groups useful in the present inventioninclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

The term “C₅-C₈cycloalkenyl” refers to a non-aromatic monocycliccarboxycyclic ring having the specified number of carbon atoms and up to3 carbon-carbon double bonds. “Cycloalkenyl” includes by way of examplecyclopentenyl and cyclohexenyl.

Where “C₃-C₈heterocycloalkyl” is used, it means a non-aromaticheterocyclic ring containing the specified number of ring atoms being,saturated or having one or more degrees of unsaturation and containingone or more heteroatom substitutions independently selected from O, Sand N. Such a ring may be optionally fused to one or more other“heterocyclic” ring(s) or cycloalkyl ring(s). Examples of “heterocyclic”moieties include, but are not limited to, aziridine, thiirane, oxirane,azetidine, oxetane, thietane, tetrahydrofuran, pyran, 1,4-dioxane,1,3-dioxane, piperidine, piperazine, 2,4-piperazinedione, pyrrolidine,imidazolidine, pyrazolidine, morpholine, thiomorpholine,tetrahydrothiopyran, tetrahydrothiophene, and the like.

“Aryl” refers to optionally substituted monocyclic and polycarbocyclicunfused or fused groups having 6 to 14 carbon atoms and having at leastone aromatic ring that complies with Hückel's Rule. Examples of arylgroups are phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl andthe like.

“Heteroaryl” means an optionally substituted aromatic monocyclic ring orpolycarbocyclic fused ring system wherein at least one ring complieswith Hückel's Rule, has the specified number of ring atoms, and thatring contains at least one heteroatom independently selected from N, Oand S. Examples of “heteroaryl” groups include furanyl, thiophenyl,pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl,quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl andindazolyl.

The term “optionally” means that the subsequently described event(s) mayor may not occur, and includes both event(s), which occur, and eventsthat do not occur.

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.Examples of suitable solvents include, but are not limited to, water,methanol, ethanol and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Examples of suitablepharmaceutically acceptable solvents include, without limitation, water,ethanol and acetic acid. Most preferably the solvent used is water.

Herein, the term “pharmaceutically-acceptable salts” refers to saltsthat retain the desired biological activity of the subject compound andexhibit minimal undesired toxicological effects. Thesepharmaceutically-acceptable salts may be prepared in situ during thefinal isolation and purification of the compound, or by separatelyreacting the purified compound in its free acid or free base form with asuitable base or acid, respectively.

By the term “co-administering” and derivatives thereof as used herein ismeant either simultaneous administration or any manner of separatesequential administration of a prolyl hydroxylase inhibiting compound,as described herein, and a further active ingredient or ingredients,known to be useful in treating diseases of the hematopoietic system,particularly anemias, including EPO or a derivative thereof. The termfurther active ingredient or ingredients, as used herein, includes anycompound or therapeutic agent known to or that demonstrates advantageousproperties when administered to a patient in need of treatment fordiseases of the hematopoietic system, particularly anemias or anycompound known to be useful when used in combination with a prolylhydroxylase inhibiting compound. Preferably, if the administration isnot simultaneous, the compounds are administered in a close timeproximity to each other. Furthermore, it does not matter if thecompounds are administered in the same dosage form, e.g. one compoundmay be administered topically and another compound may be administeredorally.

In certain embodiments, compounds according to Formula I may contain anacidic functional group, one acidic enough to form salts. Representativesalts include pharmaceutically-acceptable metal salts such as sodium,potassium, lithium, calcium, magnesium, aluminum, and zinc salts;carbonates and bicarbonates of a pharmaceutically-acceptable metalcation such as sodium, potassium, lithium, calcium, magnesium, aluminum,and zinc; pharmaceutically-acceptable organic primary, secondary, andtertiary amines including aliphatic amines, aromatic amines, aliphaticdiamines, and hydroxy alkylamines such as methylamine, ethylamine,2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine,ethanolamine, diethanolamine, and cyclohexylamine.

In certain embodiments, compounds according to Formula (I) may contain abasic functional group and are therefore capable of formingpharmaceutically-acceptable acid addition salts by treatment with asuitable acid. Suitable acids include pharmaceutically-acceptableinorganic acids and pharmaceutically-acceptable organic acids.Representative pharmaceutically-acceptable acid addition salts includehydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate,sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate,propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate,acrylate, fumnarate, malate, tartrate, citrate, salicylate,p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate,succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate,formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate,malonate, laurate, glutarate, glutamate, estolate, methanesulfonate(mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate,benzenesulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate(tosylate) and napthalene-2-sulfonate.

Compounds of formula (I) that are of particular interest include thosewherein:

X is O;

Y is O;

R¹ and R⁴ are each independently selected from the group consisting ofhydrogen, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, C₃-C₅cycloalkyl,C₃-C₈cycloalkyl-C₁-C₁₀alkyl, C₅-C₈cycloalkenyl,C₅-C₈cycloalkenyl-C₁-C₁₀alkyl, C₃-C₈heterocycloalkyl,C₃-C₈heterocycloalkyl-C₁-C₁₀alkyl, aryl, aryl-C₁-C₁₀alkyl, heteroaryland heteroaryl-C₁-C₁₀alkyl;

R² is —NR⁷R⁸ or —OR⁹;

R³ is H or C₁-C₄alkyl;

-   -   where R⁷ and Rare each independently selected from the group        consisting of hydrogen, C₁-C₁₀alkyl, C₂-C₁₀alkenyl,        C₂-C₁₀alkynyl, C₃-C₈cycloalkyl, C₃-C₈heterocycloalkyl, aryl and        heteroaryl, and    -   R⁹ is H or a cation, or C₁-C₁₀alkyl which is unsubstituted or        substituted with one or more substituents, suitably from 1 to 6        substituents, suitably from 1 to 3 substituents, independently        selected from the group consisting of C₃-C₆cycloalkyl,        heterocycloalkyl, aryl and heteroaryl;    -   where any carbon or heteroatom of R¹, R², R³, R⁴, R⁷, R⁸, R⁹ is        unsubstituted or, where possible, is substituted with one or        more substituents, suitably from 1 to 6 substituents, suitably        from 1 to 3 substituents, independently selected from        C₁-C₆alkyl, C₁-C₆haloalkyl, halogen, —OR¹⁰, —NR⁵R⁶, oxo, cyano,        nitro, —C(O)R¹⁰, —C(O)OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —NR⁵R⁶,        —CONR⁵R⁶, —N(R⁵)C(O)R¹⁰, —N(R⁵)C(O)OR¹⁰, —OC(O)NR⁵R⁶,        —N(R⁵)C(O)NR⁵R⁶, —SO₂NR⁵R⁶, —N(R⁵)SO₂R¹⁰, C₂-C₁₀alkenyl,        C₂-C₁₀alkynyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, aryl,        C₁-C₆alkyl-aryl, heteroaryl and C₁-C₆alkyl-heteroaryl, wherein        R⁵, and R⁶ are the same as defined above and R¹⁰ is selected        from hydrogen, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl,        —C(O)C₁-C₄ alkyl, —C(O)aryl, —C(O)heteroaryl,        —C(O)C₃-C₆cycloalkyl, —C(O)C₃-C₆heterocycloalkyl, —S(O)₂C₁-C₄        alkyl, C₃-C₈cycloalkyl, C₃-C₈heterocycloalkyl, C₆-C₁₄aryl,        aryl-C₁-C₁₀alkyl, heteroaryl and heteroaryl-C₁-C₁₀alkyl;        and/or a pharmaceutically acceptable salt or solvate thereof.

Compounds of formula (I) that are of further interest are those wherein:

X is O;

Y is O;

R¹ and R⁴ are each independently selected from the group consisting ofhydrogen, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, C₃-C₈cycloalkyl,C₃-C₈cycloalkyl-C₁-C₁₀alkyl, C₅-C₈cycloalkenyl,C₅-C₈cycloalkenyl-C₁-C₁₀alkyl, C₃-C₈heterocycloalkyl,C₃-C₈heterocycloalkyl-C₁-C₁₀alkyl, aryl, aryl-C₁-C₁₀alkyl, heteroaryland heteroaryl-C₁-C₁₀alkyl;

R² is —OR⁹;

R³ is H or C₁-C₄alkyl;

-   -   R⁹ is H or a cation, or C₁-C₁₀alkyl which is unsubstituted or is        substituted with one or more substituents, suitably from 1 to 6        substituents, suitably from 1 to 3 substituents, independently        selected from the group consisting of C₃-C₆ cycloalkyl,        heterocycloalkyl, aryl and heteroaryl;    -   where any carbon or heteroatom of R¹, R², R³, R⁴, R⁹ is        unsubstituted or, where possible, is substituted with one or        more substituents, suitably from 1 to 6 substituents, suitably        from 1 to 3 substituents, independently selected from        C₁-C₆alkyl, C₁-C₆haloalkyl, halogen, —OR¹⁰, —NR⁵R⁶, oxo, cyano,        nitro, —C(O)R¹⁰, —C(O)OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —NR⁵R⁶,        —CONR⁵R⁶, —N(R⁵)C(O)R¹⁰, —N(R⁵)C(O)OR¹⁰, —OC(O)NR⁵R⁶,        —N(R⁵)C(O)NR⁵R⁶, —SO₂NR⁵R⁶, —N(R⁵)SO₂R¹⁰, C₂-C₁₀ alkenyl, C₂-C₁₀        alkynyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, aryl,        C₁-C₆alkyl-aryl, heteroaryl and C₁-C₆ alkyl-heteroaryl, wherein        R⁵, and R⁶ are the same as defined above and R¹⁰ is selected        from hydrogen, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl,        —C(O)C₁-C₄alkyl, —C(O)aryl, —C(O)heteroaryl,        —C(O)C₃-C₆cycloalkyl, —C(O)C₃-C₆heterocycloalkyl,        —S(O)₂C₁-C₄alkyl, C₃-C₅cycloalkyl, C₃-C₅heterocycloalkyl,        C₆-C₁₄aryl, aryl-C₁-C₁₀alkyl, heteroaryl and        heteroaryl-C₁-C₁₀alkyl;        and/or a pharmaceutically acceptable salt or solvate thereof.

Of further interest are those compounds of formula (I) where:

X is O;

Y is O;

R¹ and R⁴ are each independently selected from the group consisting ofhydrogen, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, C₃-C₈cycloalkyl,C₃-C₈cycloalkyl-C₁-C₁₀alkyl, C₅-C₈cycloalkenyl,C₅-C₈cycloalkenyl-C₁-C₁₀alkyl, C₃-C₈heterocycloalkyl,C₃-C₈heterocycloalkyl-C₁-C₁₀alkyl, aryl, aryl-C₁-C₁₀alkyl, heteroaryland heteroaryl-C₁-C₁₀alkyl;

R² is —OR⁹;

R³ is H;

-   -   R⁹ is H or a cation;    -   where any carbon or heteroatom of R¹, R², R³, R⁴ is        unsubstituted or, where possible, is substituted with one or        more substituents, suitably from 1 to 6 substituents, suitably        from 1 to 3 substituents, independently selected from        C₁-C₆alkyl, C₁-C₆haloalkyl, halogen, —OR¹⁰, —NR⁵R⁶, oxo, cyano,        nitro, —C(O)R¹⁰, —C(O)OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —NR⁵R⁶,        —CONR⁵R⁶, —N(R⁵)C(O)R¹⁰, —N(R⁵)C(O)OR¹⁰, —OC(O)NR⁵R⁶,        —N(R⁵)C(O)NR⁵R⁶, —SO₂NR⁵R⁶, —N(R⁵)SO₂R¹⁰, C₂-C₁₀alkenyl,        C₂-C₁₀alkynyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, aryl,        C₁-C₆alkyl-aryl, heteroaryl and C₁-C₆ alkyl-heteroaryl, wherein        R⁵, and R⁶ are the same as defined above and R¹⁰ is selected        from hydrogen, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl,        —C(O)C₁-C₄alkyl, —C(O)aryl, —C(O)heteroaryl,        —C(O)C₃-C₆cycloalkyl, —C(O)C₃-C₆heterocycloalkyl, —S(O)₂C₁-C₄        alkyl, C₃-C₈ cycloalkyl, C₃-C₈heterocycloalkyl, C₆-C₁₄ aryl,        aryl-C₁-C₁₀alkyl, heteroaryl and heteroaryl-C₁-C₁₀alkyl;        and/or a pharmaceutically acceptable salt or solvate thereof.

Specific compounds that are exemplified herein and that are useful inthe present invention are:

-   N-{[1-(4-chlorophenyl)-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[1-{[2,4-bis(methyloxy)phenyl]methyl}-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[1-(4-chlorophenyl)-6-hydroxy-4-oxo-3-(phenylmethyl)-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-({6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[6-hydroxy-2,4-dioxo-1-phenyl-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(1-(1,1-dimethylethyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-(2-pyridinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[6-Hydroxy-1-(2-nitrophenyl)-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[1-[(3-Cyanophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-{[1-[(3,4-Dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[6-Hydroxy-1-{[3-(methyloxy)phenyl]methyl}-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[1-[(2,6-Dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[6-Hydroxy-1-methyl-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[1-Cyclohexyl-3-(2-cyclopropylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(1,3-Dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-{[1-Hexyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[1-Ethyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-propyl-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[1-Butyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[6-Hydroxy-2,4-dioxo-1-(2-phenylethyl)-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[3-{[4-(1,1-Dimethylethyl)phenyl]methyl}-6-hydroxy-1-(1-methylethyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(1-cyclohexyl-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-{[6-Hydroxy-1,3-bis(1-methylethyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[3-[(2-Bromophenyl)methyl]-1-(1,1-dimethylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(1-(2,6-Dichlorophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-[(1-(2,4-dichlorophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-[(1-(2-Bromophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-[(1-(2-Biphenylyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[3-{[4-(1,1-Dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1-(2-thienyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-({1-Cyclohexyl-6-hydroxy-3-[3-(4-morpholinyl)propyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[3-{[4-(1,1-Dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1-(3-pyridinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-({1-Cyclohexyl-3-[(2-fluorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-({3-[(2-Chlorophenyl)methyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-({1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-({1-Cyclohexyl-3-[(2,4-dimethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-({1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-[(2,4,6-trifluorophenyl)methyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-[(1-Cyclohexyl-6-hydroxy-3-{[4-(1-methylethyl)phenyl]methyl}-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-({1-Cyclohexyl-3-[(2-ethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-({1-Cyclohexyl-3-[(4-ethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-({1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-[(2,4,6-trimethylphenyl)methyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[1-Cyclohexyl-3-(2-cyclohexylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(3-{[3,5-Bis(methyloxy)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-{[1-Cyclohexyl-6-hydroxy-3-(2-naphthalenylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-({1-Cyclohexyl-6-hydroxy-3-[(4-methylphenyl)methyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[3-(4-Biphenylylmethyl)-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(3-{[4-(1,3-Benzoxazol-2-yl)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-({3-[2-(4-Biphenylyl)-2-oxoethyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-[(1,3-Bis{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-{[1-Cyclohexyl-6-hydroxy-3-(4-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-({1-Cyclohexyl-3-[4-(1,1-dimethylethyl)cyclohexyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-[(1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-({1-Cyclohexyl-3-[4-(1,1-dimethylethyl)phenyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[1-Cyclohexyl-3-(cyclohexylmethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(3-Cycloheptyl-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-[(3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-tricyclo[3,3,1,1^(3,7)]dec-1-yl-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-({1-[(1R,2R,4S)-Bicyclo[2,2,1]hept-2-yl]-3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[1-Cyclohexyl-6-hydroxy-3-(3-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(3-Cyclohexyl-1-cyclopropyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-[(1-Cyclobutyl-3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-[(3-Cyclohexyl-1-cyclopentyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-{[6-Hydroxy-1,3-bis(3-methylbutyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(6-Hydroxy-1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-({1,3-Bis[(2-chlorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-[(1,3-Dihexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-{[1-Cyclohexyl-6-hydroxy-3-(2-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[1-Cyclohexyl-6-hydroxy-3-(2-naphthalenyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(1-Cyclohexyl-3-hexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-[(1,3-Dicycloheptyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-[(1,3-Dicyclopentyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-{[1-Cyclohexyl-3-(2,3-dimethylcyclohexyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   4-[5-{[(Carboxymethyl)amino]carbonyl}-3-cyclohexyl-4-hydroxy-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]cyclohexanecarboxylic    acid;-   N-{[1-Cyclohexyl-3-(4-ethylcyclohexyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   cis-4-[3-Cyclohexyl-5-({[2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-4-hydroxy-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]cyclohexanecarboxylic    acid;-   N-{[1-Cyclohexyl-6-hydroxy-3-(1-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   3-[5-{[(Carboxymethyl)amino]carbonyl}-3-cyclohexyl-4-hydroxy-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]cyclohexanecarboxylic    acid;-   N-{[1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-(2-oxo-2-phenylethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(1-Cyclohexyl-6-hydroxy-3-{2-[4-(methyloxy)phenyl]-2-oxoethyl}-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-({1-Cyclohexyl-6-hydroxy-3-[2-(4-methylphenyl)-2-oxoethyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[1-Cyclohexyl-3-(3,3-dimethyl-2-oxobutyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-({1-Cyclohexyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-({3-[2-(4-Cyanophenyl)-2-oxoethyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-({3-[2-(1-Benzofuran-2-yl)-2-oxoethyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[3-Cyclohexyl-6-hydroxy-1-(1-naphthalenyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[3-Cyclohexyl-1-(4,4-dimethylcyclohexyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-({1-Cyclohexyl-3-[(2,3-difluorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   Ethyl    N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonothioyl]glycinate;-   N-[(1,3-Dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonothioyl]glycine;-   6-[5-{[(Carboxymethyl)amino]carbonyl}-3-cyclohexyl-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]hexanoic    acid;-   6-[5-{[(Carboxymethyl)amino]carbonothioyl}-3-cyclohexyl-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]hexanoic    acid;-   N-({1-Cyclohexyl-3-[(3,4-dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-[(1-Cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-({3-Cyclohexyl-6-hydroxy-1-[trans-4-(methyloxy)cyclohexyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-({1-[1,1′-Bi(cyclohexyl)-4-yl]-3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[6-Hydroxy-2,4-dioxo-1,3-bis(1-propylbutyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-({3-(2-Cyclopropylethyl)-6-hydroxy-1-[3-(methyloxy)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(4-phenylcyclohexyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-({1-Cyclohexyl-3-[(3,4-difluorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-({3-(2-Cyclopropylethyl)-6-hydroxy-1-[4-(methyloxy)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[3-(2-Cyclopropylethyl)-6-hydroxy-1-(3-nitrophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-({3-(2-Cyclopropylethyl)-6-hydroxy-2,4-dioxo-1-[4-(2-thienyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[1,3-Bis(1-ethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(6-Hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-[(1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-[(1,3-Dibutyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-{[1,3-Bis(2-cyclopropylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[6-Hydroxy-1,3-bis(2-methylpropyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-({3-(2-Cyclopropylethyl)-6-hydroxy-1-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-({3-(2-Cyclopropylethyl)-6-hydroxy-1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(4-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-({3-(2-Cyclopropylethyl)-1-[4-(2-furanyl)phenyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[1,3-Bis(1,1-dimethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(1-{[(phenylmethyl)oxy]carbonyl}-3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-{[1-(1-Acetyl-3-piperidinyl)-3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;-   N-[(1-Cyclohexyl-3-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-({3-[(2-Bromophenyl)methyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-({1-Cyclohexyl-3-[(2,6-dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-[(3-{[2-Bromo-5-(methyloxy)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-[(3-{[2,4-Bis(trifluoromethyl)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-({3-[(2-Bromo-5-fluorophenyl)methyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-[(3-{[2-Bromo-4-(1,1-dimethylethyl)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine;-   N-({1-Cyclohexyl-6-hydroxy-3-[(2-methylphenyl)methyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine;-   N-{[1-Cyclohexyl-3-(1,1-dimethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine;    and-   N-{[1,3-Bis(2,6-dichlorophenyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.

Processes for preparing the compound of formula (I) are also within theambit of this invention. To illustrate, a process for preparing acompound of formula (I)

wherein X, Y, R¹, R², R³ and R⁴ are the same as defined above forformula (I), the process comprising treating a compound of formula A:

wherein R¹ and R⁴ are the same as for those groups in formula (I) withglycine and an appropriate base, such as1,8-diazabicyclo[5.4.0]undec-7-ene, in an appropriate solvent, such asethanol, under either conventional thermal conditions or by microwaveirradiation, to form a compound of formula (I) where Y is O, R² is —OH,and R³ is H;

or a process for preparing a compound of formula (I) wherein X, Y, R¹,R², R³ and R⁴ are the same as defined above for formula (I), the processcomprising treating a compound of formula B:

wherein X, Y, R¹, R², R³ and R⁴ are the same as for those groups informula (I) with an alkali such as sodium hydroxide, in an appropriatesolvent, such as aqueous ethanol, at a suitable temperature such as roomtemperature, to form a compound of formula (I) where R² is —OH;

or a process for preparing a compound of formula (I) wherein X, Y, R¹,R², R³ are the same as defined above for formula (I) and R⁴ ispiperidinyl, the process comprising treating a compound of formula C:

wherein X, Y, R¹, and R³ are the same as for those groups in formula (I)with an acylating agent such as acetic anhydride, in an appropriatesolvent, such as acetic acid, at a suitable temperature such as 130° C.,to form a compound of formula (I) where R² is —OH, and R⁴ isacylpiperidinyl;

It will be appreciated by those skilled in the art that the compounds offormula (I) may exist in one or more tautomeric forms such as:

All tautomeric forms of the compounds described herein, includingmixtures thereof, are intended to be encompassed within the scope of theinvention. Generally, the compounds exemplified herein have beenassigned names based on the structure of the tautomer of formula (IA).It should be understood that any reference to named compounds of thisinvention is intended to encompass all tautomers of the named compoundsand any mixtures of tautomers of the named compounds.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and, if crystalline, may optionally be solvated,e.g. as the hydrate. This invention includes within its scopestoichiometric solvates (e.g. hydrates) as well as compounds containingvariable amounts of solvent (e.g. water).

Certain of the compounds described herein may contain one or more chiralatoms, or may otherwise be capable of existing as two enantiomers. Thecompounds claimed below include mixtures of enantiomers as well aspurified enantiomers or enantiomerically enriched mixtures. Alsoincluded within the scope of the invention are the individual isomers ofthe compounds represented by formula (I), or claimed below, as well asany wholly or partially equilibrated mixtures thereof. The presentinvention also covers the individual isomers of the claimed compounds asmixtures with isomers thereof in which one or more chiral centers areinverted.

Where there are different isomeric forms they may be separated orresolved one from the other by conventional methods, or any given isomermay be obtained by conventional synthetic methods or by stereospecificor asymmetric syntheses.

While it is possible that, for use in therapy, a compound of formula(I), as well as salts, solvates and the like, may be administered as aneat preparation, i.e. no additional carrier, the more usual practice isto present the active ingredient confected with a carrier or diluent.Accordingly, the invention further provides pharmaceutical compositions,which includes a compound of formula (I) and salts, solvates and thelike, and one or more pharmaceutically acceptable carriers, diluents, orexcipients. The compounds of formula (I) and salts, solvates, etc, areas described above. The carrier(s), diluent(s) or excipient(s) must beacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Inaccordance with another aspect of the invention there is also provided aprocess for the preparation of a pharmaceutical formulation includingadmixing a compound of the formula (I), or salts, solvates etc, with oneor more pharmaceutically acceptable carriers, diluents or excipients.

It will be appreciated by those skilled in the art that certainprotected derivatives of compounds of formula (I), which may be madeprior to a final deprotection stage, may not possess pharmacologicalactivity as such, but may, in certain instances, be administered orallyor parenterally and thereafter metabolised in the body to form compoundsof the invention which are pharmacologically active. Such derivativesmay therefore be described as “prodrugs”. Further, certain compounds ofthe invention may act as prodrugs of other compounds of the invention.All protected derivatives and prodrugs of compounds of the invention areincluded within the scope of the invention. It will further beappreciated by those skilled in the art, that certain moieties, known tothose skilled in the art as “pro-moieties” may be placed on appropriatefunctionalities when such functionalities are present within compoundsof the invention. Preferred prodrugs for compounds of the inventioninclude: esters, carbonate esters, hemi-esters, phosphate esters, nitroesters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds,phosphamides, glycosides, ethers, acetals and ketals.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I),depending on the condition being treated, the route of administrationand the age, weight and condition of the patient, or pharmaceuticalcompositions may be presented in unit dose forms containing apredetermined amount of active ingredient per unit dose. Preferred unitdosage compositions are those containing a daily dose or sub-dose, asherein above recited, or an appropriate fraction thereof, of an activeingredient. Furthermore, such pharmaceutical compositions may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such compositions maybe prepared by any method known in the art of pharmacy, for example bybringing into association a compound of formal (I) with the carrier(s)or excipient(s).

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by tablet forming dies by means ofthe addition of stearic acid, a stearate salt, tale or mineral oil. Thelubricated mixture is then compressed into tablets. The compounds of thepresent invention can also be combined with a free flowing inert carrierand compressed into tablets directly without going through thegranulating or slugging steps. A clear or opaque protective coatingconsisting of a sealing coat of shellac, a coating of sugar or polymericmaterial and a polish coating of wax can be provided. Dyestuffs can beadded to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of a compound of formula (I). Syrups can be prepared bydissolving the compound in a suitably flavored aqueous solution, whileelixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a non-toxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxy ethylene sorbitol ethers, preservatives, flavoradditive such as peppermint oil or natural sweeteners or saccharin orother artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit pharmaceutical compositions for oraladministration can be microencapsulated. The formulation can also beprepared to prolong or sustain the release as for example by coating orembedding particulate material in polymers, wax or the like.

Pharmaceutical compositions adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical compositions adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe composition isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The pharmaceutical compositions may bepresented in unit-dose or multi-dose containers, for example sealedampoules and vials, and may be stored in a freeze-dried (lyophilized)condition requiring only the addition of the sterile liquid carrier, forexample water for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the pharmaceutical compositions may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavouring agents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the intended recipient, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe route of administration, and will ultimately be at the discretion ofthe attendant prescribing the medication. However, an effective amountof a compound of formula (I) for the treatment of anemia will generallybe in the range of 0.001 to 100 mg/kg body weight of recipient per day,suitably in the range of 0.01 to 10 mg/kg body weight per day. For a 70kg adult mammal, the actual amount per day would suitably be from 7 to700 mg and this amount may be given in a single dose per day or in anumber (such as two, three, four, five or six) of sub-doses per day suchthat the total daily dose is the same. An effective amount of a salt orsolvate, etc., may be determined as a proportion of the effective amountof the compound of formula (I) per se. It is envisaged that similardosages would be appropriate for treatment of the other conditionsreferred to above.

Definitions

CDI—carbonyl di-imidazole

DBU—1,8-diazabicyclo[5.4.0]undec-7-ene

DIAD—diisopropyl azodicarboxylate

DMA—N,N-dimethylacetamide

DMF—N,N-dimethylformamide

DMSO—dimethylsulfoxide

HPLC—high pressure liquid chromatography

LC/MS—liquid chromatography/mass spectrometry

NMR—nuclear magnetic resonance

rt—room temperature

TFA—Trifluoroacetic acid

THF—tetrahydrofuran

Chemical Background

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention as prepared are given in theexamples.

Compounds of general formula (I) may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1991) ProtectingGroups in Organic Synthesis, John Wiley & Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprocesses as well as the reaction conditions and order of theirexecution shall be consistent with the preparation of compounds offormula (I). Those skilled in the art will recognize if a stereocenterexists in compounds of formula (I). Accordingly, the present inventionincludes both possible stereoisomers and includes not only racemiccompounds but the individual enantiomers as well. When a compound isdesired as a single enantiomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be effected by any suitable method known in theart. See, for example, Stereochemistry of Organic Compounds by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

Illustrated Methods of Preparation

-   -   a) 1. NaH, THF, rt 2. R¹NCO, 60° C.; b) 1. NaH, THF or dioxane,        rt 2. R⁴NCX, heat; c) H₂NCH₂CO₂H, DBU, EtOH, 160° C., microwave.

EXPERIMENTALS Example 1

N-{[1-(4-Chlorophenyl)-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

1a). Diethyl {[(phenylmethyl)amino]carbonyl}propanedioate. A solution ofdiethyl malonate (1.52 mL, 10.0 mmoles) in dry tetrahydrofuran (20 mL)was added to a suspension of sodium hydride (60% suspension in mineraloil, 500 mg, 12.5 mmoles) under argon atmosphere at room temperature.After stirring for 15 minutes, a solution of benzyl isocyanate (1.33 mL,10.0 mmoles) was added and the mixture was heated at 60° C. for 3 hours.The mixture was cooled, carefully acidified with 1 molar hydrochloricacid and the tetrahydrofuran evaporated. The mixture was diluted withwater and extracted twice with chloroform. The combined extracts werewashed twice with brine, dried and evaporated. Crystallization fromether-hexane afforded the title compound as a white solid, 1.2 g, 40%.1H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J=7.20 Hz, 6H) 4.11-4.20 (m,4H) 4.33 (d, J=6.06 Hz, 2H) 4.56 (s, 1H) 7.24 (s, 1H) 7.25-7.36 (m, 5H)8.74 (t, J=5.68 Hz, 1H).

1b) Ethyl1-(4-chlorophenyl)-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.Diethyl {[(phenylmethyl)amino]carbonyl}propanedioate (293 mg, 1.0mmoles) was added to a suspension of sodium hydride (60% suspension inmineral oil, 100 mg, 2.5 mmoles) in dry tetrahydrofuran (50 mL) andstirred for 10 minutes under argon. 4-Chlorophenyl isocyanate was addedand the mixture was heated under reflux for 2 hours, cooled, acidifiedwith 1 molar hydrochloric acid and extracted with ethyl acetate. Flashchromatography (hexane-ethyl acetate) afforded the title compound (225mg, 56%) 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (t, J=7.07 Hz, 3H) 3.45(q, J=7.07 Hz, 2H) 5.00 (s, 2H) 7.25-7.28 (m, 1H) 7.30-7.37 (m, 6H) 7.53(d, J=8.59 Hz, 2H).

1c)N-{[1-(4-Chlorophenyl)-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of ethyl1-(4-chlorophenyl)-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate(225 mg, 0.56 mmoles), DBU (200 mg, 1.31 mmoles) and glycine (100 mg,1.33 mmoles) in ethanol (10 mL) was sealed in a flask and heated in amicrowave reactor at 160° C. for 1 hour. The reaction mixture wasevaporated, dissolved in chloroform and washed with 1 molar hydrochloricacid. Evaporation of the residue and separation by preparative HPLC(10-80% acetonitrile-water-0.1% TFA) afforded the title compound (25 mg,10%) 1H NMR (400 MHz, DMSO-d₆) δ ppm 4.13 (d, J=5.81 Hz, 2H) 5.03 (s,2H) 7.24-7.29 (m, 1H) 7.31-7.38 (m, 4H) 7.42 (d, J=8.34 Hz, 2H)7.52-7.58 (m, 2H) 10.07 (s, 1H) 13.11 (s, 1H)

Example 2

N-{[1-{[2,4-Bis(methyloxy)phenyl]methyl}-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

2a) Ethyl1-{[2,4-bis(methyloxy)phenyl]methyl}-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.Diethyl {[(phenylmethyl)amino]carbonyl}propanedioate (820 mg, 2.8mmoles) was added to a suspension of sodium hydride (60% suspension inmineral oil, 280 mg, 7.0 mmoles) in dry tetrahydrofuran (50 mL) andstirred for 10 minutes under argon. 2,4-dimethoxybenzyl isocyanate (1.0mL, 6.0 mmoles) was added and the mixture heated under reflux for 3hours, cooled, acidified with 1 molar hydrochloric acid and extractedwith ethyl acetate. Flash chromatography (30% methanol indichloromethane) afforded the title compound (480 mg, 39%) 1H NMR (400MHz, DMSO-d₆) δ ppm 1.15 (t, J=6.69 Hz, 3H) 3.71 (s, 3H) 3.78 (s, 3H)4.09 (q, J=5.05 Hz, 1H) 4.81 (s, 2H) 4.92 (s, 2H) 6.40-6.59 (m, 3H)6.62-7.26 (m, 5H).

2b)N-{[1-{[2,4-bis(methyloxy)phenyl]methyl}-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of ethyl1-{[2,4-bis(methyloxy)phenyl]methyl}-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate(110 mg, 0.25 mmoles), DBU (76 mg, 0.5 mmoles) and glycine (38 mg, 0.5mmoles) in ethanol (5 mL) was sealed in a flask and heated in amicrowave reactor at 160° C. for 1 hour. The reaction mixture wasdiluted with 1 molar hydrochloric acid and extracted with ethyl acetate.Purification by preparative HPLC (10-80% acetonitrile-water-0.1% TFA)afforded the title compound (50 mg, 42%) 1H NMR (400 MHz, DMSO-d₆) δ ppm3.71-3.81 (m, 6H) 4.13 (d, J=5.31 Hz, 2H) 4.92 (s, 2H) 5.03 (s, 2H)6.39-6.49 (m, 1H) 6.56 (s, 1H) 6.81 (d, J=8.08 Hz, 1H) 7.24-7.36 (m, 5H)10.10 (s, 1H) 13.10 (s, 1H)

Example 3

N-{[1-(4-Chlorophenyl)-6-hydroxy-4-oxo-3-(phenylmethyl)-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

3a) Ethyl1-(4-chlorophenyl)-6-hydroxy-4-oxo-3-(phenylmethyl)-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.Diethyl {[(phenylmethyl)amino]carbonyl}propanedioate (400 mg, 1.36mmoles) was added to a suspension of sodium hydride (60% suspension inmineral oil, 200 mg, 5.0 mmoles) in dry dioxan (15 mL) and stirred for10 minutes under argon. 4-Chlorophenyl isothiocyanate (340 mg, 2.0mmoles) was added and the mixture sealed in a pressure flask heated in amicrowave reactor at 100° C. for 1 hour. The mixture was taken up indichloromethane, washed with 1 molar hydrochloric acid and dried. Flashchromatography (hexane-ethyl acetate) afforded the title compound (85mg, 20%) 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (t, J=7.20 Hz, 3H)4.01-4.06 (q, J=7.20 Hz, 2H) 4.89 (s, 2H) 7.10 (d, J=8.59 Hz, 2H)7.26-7.31 (m, 5H) 7.39 (d, J=8.59 Hz, 2H).

3b)N-{[1-(4-Chlorophenyl)-6-hydroxy-4-oxo-3-(phenylmethyl)-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of ethyl1-(4-chlorophenyl)-6-hydroxy-4-oxo-3-(phenylmethyl)-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate(85 mg, 0.21 mmoles), DBU (90 mg, 0.6 mmoles) and glycine (60 mg, 0.8mmoles) in ethanol (5 mL) was sealed in a flask and heated in amicrowave reactor at 160° C. for 1 hour. The reaction mixture wasdiluted with 1 molar hydrochloric acid and extracted twice with ethylacetate. The combined extracts were washed with 1 molar hydrochloricacid, dried and evaporated. Purification by preparative HPLC (10-80%acetonitrile-water-0.1% TFA) afforded the title compound (23 mg, 24%) 1HNMR (400 MHz, DMSO-d₆) δ ppm 4.14 (d, J=5.81 Hz, 2H) 5.67 (s, 2H) 7.24(t, J=6.95 Hz, 1H) 7.29-7.40 (m, 7H) 7.54 (d, J=8.59 Hz, 2H) 10.10 (s,1H) 13.11 (s, 1H)

Example 4

N-({6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

4a) Ethyl6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.Diethyl {[(phenylmethyl)amino]carbonyl}propanedioate (200 mg, 0.68mmoles) was added to a suspension of sodium hydride (60% suspension inmineral oil, 100 mg, 2.5 mmoles) in dry dioxane (5 mL) and stirred for10 minutes under argon. 3-Trifluorophenyl isocyanate (140 uL, 1.02mmoles) was added and the mixture sealed in a pressure flask heated in amicrowave reactor at 100° C. for 40 minutes. The mixture was taken up indichloromethane, washed with 1 molar hydrochloric acid and dried. Themixture was evaporated and azeotroped with ethanol. The residue wasslurried in diethyl ether to give the title compound (110 mg, 37%) 1HNMR (400 MHz, DMSO-d₆) δ ppm 1.10 (t, J=6.95 Hz, 3H) 3.39 (q, J=6.99 Hz,2H) 4.89-4.94 (m, 2H) 7.18-7.23 (m, 2H) 7.24-7.31 (m, 3H) 7.44-7.55 (m,2H) 7.59-7.69 (m, 2H).

4b)N-({6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine.A mixture of ethyl6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate(110 mg, 0.25 mmoles), DBU (100 mg, 0.6 mmoles) and glycine (40 mg, 0.5mmoles) in ethanol (5 mL) was sealed in a flask and heated in amicrowave reactor at 160° C. for 1 hour. The reaction mixture wasdiluted with 1 molar hydrochloric acid and extracted twice withdichloromethane. Purification by preparative HPLC (10-80%acetonitrile-water-0.1% TFA) afforded the title compound (15 mg, 13%) 1HNMR (400 MHz, DMSO-d₆) δ ppm 3.79 (d, J=5.05 Hz, 2H) 4.97 (s, 2H)7.19-7.30 (m, 5H) 7.46-7.57 (m, 2H) 7.60-7.71 (m, 2H) 8.27 (s, 1H) 9.60(s, 1H)

Example 5

N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

5a) Ethyl6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.Ethyl1-{[2,4-bis(methyloxy)phenyl]methyl}-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate(260 mg, 0.59 mmoles) was stirred in a mixture of sulfuric acid (5.0 mL)and water (1.0 mL) for 3 hours. The mixture was poured onto ice and thesolid collected.

The aqueous was adjusted to pH3 and extracted three times with ethylacetate. The extracts were dried, evaporated and combined with thecollected solid. Purification by preparative HPLC(acetonitrile-water-0.1% TFA) gave the title compound (106 mg, 62%) 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.07 Hz, 3H) 4.14 (q,J=7.16 Hz, 2H) 5.09 (s, 1H) 5.14 (s, 1H) 7.25-7.37 (m, 3H) 7.42-7.52 (m,2H) 10.22 (s, 1H) 15.53 (s, 1H).

5b)N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of ethyl6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate(100 mg, 0.34 mmoles), DBU (106 mg, 0.7 mmoles) and glycine (52 mg, 0.7mmoles) in ethanol (5 mL) was sealed in a flask and heated in amicrowave reactor at 160° C. for 1 hour. The reaction mixture was takenup in ethyl acetate and washed with 1 molar hydrochloric acid.Purification by preparative HPLC (10-80% acetonitrile-water-0.1% TFA)afforded the title compound (15 mg, 14%) 1H NMR (400 MHz, DMSO-d₆) δ ppm4.11 (s, 2H) 4.95 (s, 2H) 7.23-7.35 (m, 5H) 9.84 (s, 1H) 12.09 (s, 1H)

Example 6

N-{[6-Hydroxy-2,4-dioxo-1-phenyl-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

6a) Ethyl6-hydroxy-2,4-dioxo-1-phenyl-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.Diethyl {[(phenylmethyl)amino]carbonyl}propanedioate (420 mg, 1.43mmoles) was added to a suspension of sodium hydride (60% suspension inmineral oil, 220 mg, 5.5 mmoles) in dry dioxan (10 mL) and stirred for10 minutes under argon. Phenyl isocyanate (240 uL, 2.21 mmoles) wasadded and the mixture sealed in a pressure flask heated in a microwavereactor at 110° C. for 1 hour. The mixture was taken up indichloromethane, washed with 1 molar hydrochloric acid and evaporatedonto silica gel. Flash chromatography (ethyl acetate) gave the titlecompound (300 mg, 57%) 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (t, J=7.07Hz, 3H) 3.99-4.07 (q, J=7.07 Hz, 2H) 4.94 (s, 1H) 7.08-7.13 (m, 2H) 7.21(ddd, J=8.46, 4.42, 4.29 Hz, 1H) 7.26-7.33 (m, 5H) 7.37 (t, J=7.45 Hz,2H).

6b)N-{[6-Hydroxy-2,4-dioxo-1-phenyl-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of ethyl6-hydroxy-2,4-dioxo-1-phenyl-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate(300 mg, 0.82 mmoles), DBU (150 mg, 1.0 mmoles) and glycine (120 mg, 1.6mmoles) in ethanol (15 mL) was sealed in a flask and heated in amicrowave reactor at 160° C. for 1 hour. The reaction mixture wasfiltered and the filtrate diluted with dichloromethane and washed with 1molar hydrochloric acid. The aqueous was extracted with dichloromethaneand the combined extracts dried and evaporated to give the titlecompound (50 mg, 15%) 1H NMR (400 MHz, DMSO-d₆) δ ppm 3.81 (s, 2H) 4.99(s, 2H) 7.14 (d, J=7.33 Hz, 2H) 7.19-7.23 (m, 1H) 7.25-7.34 (m, 5H) 7.39(t, J=7.45 Hz, 2H) 9.84 (s, 1H)

Example 7

N-[(1-(1,1-Dimethylethyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

7a)1-(1,1-Dimethylethyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione.A mixture of t-butyl isocyanate (571 uL, 5.0 mmoles) and4-t-butylbenzylamine (880 uL, 5.0 mmoles) in dry dichloromethane wasstirred for 1 hour. Dichloromalonate (486 uL, 5.0 mmoles) was added andthe mixture was heated under reflux for 1 hour. The mixture was washedwith 1N hydrochloric acid and evaporated onto silica gel. Flashchromatography (10-35% ethyl acetate-hexane) gave the title compound(1.3 g, 79%) 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (s, 9H) 1.63 (s,9H) 3.60 (s, 2H) 4.99 (s, 2H) 7.37 (d, J=2.78 Hz, 4H).

7b) EthylN-[(1-(1,1-dimethylethyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate.1-(1,1-Dimethylethyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione(1.3 g, 3.93 mmoles) and diisopropylethylamine (1.36 mL, 7.86 mmoles)were stirred together in dry chloroform (25 mL) and treated with ethylisocyanatoacetate (335 uL, 3.93 mmoles). The mixture was stirred for 3hours, washed twice with 1 molar hydrochloric acid, dried and evaporatedto give the title compound (1.8 g, quant.) 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.32 (t, J=7.07 Hz, 3H) 1.71 (s, 9H) 1.73 (s, 9H)4.28-4.34 (m, 2H) 5.03-5.07 (m, 2H) 7.33-7.39 (m, 4H) 10.21-10.30 (m,1H).

7c)N-[(1-(1,1-Dimethylethyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.A mixture of ethylN-[(1-(1,1-dimethylethyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(1.8 g, 3.9 mmoles) and 1 molar sodium hydroxide solution (6.0 mL) inethanol (5.0 mL) was stirred overnight. The reaction was incomplete;therefore 6 molar sodium hydroxide was added. After 2 hours, the mixturewas partitioned between ethyl acetate and 1 molar hydrochloric acid, theorganic solution washed with 1 molar hydrochloric acid, dried andevaporated. The title compound was obtained by crystallization from coldhexane (700 mg, 41%) 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (s, 9H) 1.65(s, 9H) 4.11 (d, J=5.81 Hz, 2H) 4.93 (s, 2H) 7.20 (d, J=8.59 Hz, 2H)7.34 (d, J=8.34 Hz, 2H) 10.06 (t, J=5.56 Hz, 1H) 13.06 (s, 1H).

Example 8

N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-(2-pyridinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

8a) 2-Isocyanatopyridine. 2-Picolinic acid (1.0 g, 8.0 mmoles) wasstirred in toluene (25 mL) and treated with diphenylphosphoryl azide(2.0 mL, 9.3 mmoles) at room temperature under argon. Triethylamine(1.34 mL, 9.6 mmoles) was added dropwise, stirred for 30 minutes thenheated to 80° C. for 2 hours. The mixture was cooled, the solidcollected, washed with a little ethyl acetate, hexane and vacuum driedto give the title compound (750 mg, 78%) 1H NMR (400 MHz, DMSO-d₆) δ ppm8.62 (dd, J=4.93, 1.14 Hz, 1H), 8.44 (d, J=6.32 Hz, 1H), 8.04 (td,J=7.71, 2.02 Hz, 1H), 7.91 (ddd, J=8.84, 6.95, 1.64 Hz, 1H), 7.55 (s,1H), 7.51-7.55 (m, 1H), 7.17 (d, J=8.84 Hz, 1H), 7.00 (td, J=6.95, 1.26Hz, 1H).

8b) Ethyl6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-(2-pyridinyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.2-Isocyanatopyridine (265 mg, 2.2 mmoles) was added to a suspension ofsodium hydride (200 mg, 5 mmoles) and diethyl{[(phenylmethyl)amino]carbonyl}propanedioate (example 1a, 425 mg, 1.45mmoles) in anhydrous dioxane (10 mL). The mixture was heated in amicrowave reactor at 110° C. for 1 hour, cooled, dissolved indichloromethane, washed with 1 molar hydrochloric acid and purified byflash chromatography (ethyl acetate-10% methanol in ethyl acetate) togive the title compound (90 mg, 12%) 1H NMR (400 MHz, DMSO-d₆) δ ppm8.93 (dd, J=7.20, 1.39 Hz, 1H), 8.11-8.26 (m, 1H), 7.19-7.45 (m, 7H),4.78-5.01 (m, 2H), 4.15 (q, J=7.24 Hz, 2H), 1.24 (t, J=7.07 Hz, 3H).

8c)N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-(2-pyridinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture ofN-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-(2-pyridinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine(90 mg, 0.24 mmoles), glycine (90 mg, 1.2 mg) and DBU (150 mg, 1.0mmoles) in ethanol (5 mL) was heated at 170° C. for 1 hour in amicrowave reactor. Purification by preparative HPLC (acetonitrile-0.1%TFA in water, 20-100%) gave the title compound (17 mg, 18%). 1H NMR (400MHz, DMSO-d₆) δ ppm 13.13 (s, 1H), 10.07 (s, 1H), 8.58 (dd, J=4.93, 1.14Hz, 1H), 8.01 (td, J=7.71, 1.77 Hz, 1H), 7.49-7.58 (m, 2H), 7.26-7.36(m, 6H), 5.02 (s, 2H), 4.15 (d, J=5.81 Hz, 2H).

Example 9

N-{[6-Hydroxy-1-(2-nitrophenyl)-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

9a) Ethyl6-hydroxy-1-(2-nitrophenyl)-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.Diethyl {[(phenylmethyl)amino]carbonyl}propanedioate (420 mg, 1.43mmoles) was added to a suspension of sodium hydride (60% suspension inmineral oil, 220 mg, 5.5 mmoles) in dry dioxan (10 mL) and stirred for10 minutes under argon. 2-Nitrophenyl isocyanate (360 mg, 2.20 mmoles)was added and the mixture sealed in a pressure flask heated in amicrowave reactor at 110° C. for 1 hour. The mixture was taken up indichloromethane, washed with 1 molar hydrochloric acid and evaporatedonto silica gel. Flash chromatography (hexane to 0.5% formic acid inethyl acetate) gave the title compound (59 mg, 7%) 1H NMR (400 MHz,DMSO-d₆) δ ppm 8.16 (s, 1H), 7.81 (s, 1H), 7.68 (s, 1H), 7.47 (s, 1H),7.08-7.38 (m, 5H), 4.77-5.16 (m, 2H), 4.12 (q, J=5.31 Hz, 2H), 0.97-1.31(m, 3H)

9b)N-{[6-Hydroxy-2,4-dioxo-1-phenyl-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of ethyl6-hydroxy-1-(2-nitrophenyl)-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate(59 mg, 0.14 mmoles), DBU (80 mg, 0.52 mmoles) and glycine (40 mg, 0.53mmoles) in ethanol (3 mL) was sealed in a flask and heated in amicrowave reactor at 170° C. for 1 hour. The reaction mixture was pouredinto 1 molar hydrochloric acid and extracted with dichloromethane (×2)and washed with 1 molar hydrochloric acid. The title compound wasobtained by purification by preparative HPLC (10-80%acetonitrile-water-0.1% TFA)(17 mg, 28%) 1H NMR (400 MHz, DMSO-d₆) δ ppm13.14 (br. s., 1H), 10.04 (br. s., 1H), 8.25 (dd, J=8.21, 1.14 Hz, 1H),7.93 (dt, J=7.71, 1.26 Hz, 1H), 7.71-7.81 (m, 2H), 5.06 (s, 2H), 4.14(d, J=5.56 Hz, 2H)

Example 10

N-{[1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

A microwave tube containing sodium hydride (60% suspension in oil, 46mg, 1.15 mmoles) in dioxan (3 mL) was treated with diethyl{[(phenylmethyl)amino]carbonyl}-propanedioate (example 1a, 100 mg, 0.34mmoles) and stirred under argon until evolution ceased. Cyclohexylisocyanate (90 uL, 0.7 mmoles) was added and the mixture was heated at100° C. for 30 minutes in a microwave reactor. Glycine (48 mg, 0.65mmoles) and DBU (4 drops) was added, the flask re-sealed and heated at160° C. for 1 hour in a microwave reactor. The mixture was poured into 1molar hydrochloric acid and extracted with dichloromethane (×3). Thecombined extracts were washed with 1 molar hydrochloric acid and brine,dried and evaporated to give the crude product. Purification bypreparative HPLC (acetonitrile-water-0.1% TFA, 20-100%) gave the titlecompound (10 mg, 7%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 10.12 (t, J=5.18Hz, 1H), 7.23-7.34 (m, 6H), 4.99 (s, 2H), 4.65 (t, J=11.62 Hz, 1H), 4.10(d, J=5.81 Hz, 2H), 2.21-2.32 (m, 2H), 1.78 (d, J=12.63 Hz, 2H), 1.62(s, 3H), 1.22-1.33 (m, 3H), 1.06-1.17 (m, 1H)

Example 11

N-{[1-[(3-Cyanophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

11a) EthylN-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate.Ethyl isocyanatoacetate (2.24 mL, 20 mmoles) was added dropwise to asolution of 1-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (4.4 g, 20mmoles) and ethyl diisopropylamine (6.9 mL, 40 mmoles) indichloromethane (120 mL) and stirred overnight under argon. The mixturewas washed with 1 molar hydrochloric acid, water and brine, dried andevaporated. The solid was slurried in diethyl ether, collected, washedwith diethyl ether and hexane, dried to give the title compound (5.1 g,73%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 12.13 (br. s., 1H), 9.84 (br. s.,1H), 7.13-7.48 (m, 5H), 4.95 (s, 2H), 4.17 (d, 2H), 4.15 (q, 2H), 1.21(t, J=7.20 Hz, 3H)

11b) EthylN-{[1-[(3-cyanophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate.A mixture of ethylN-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate(350 mg, 1.0 mmoles), 3-cyanobenzyl bromide (250 mg, 1.22 mmoles) andsodium carbonate (300 mg, 2.9 mmoles) in dimethylformamide (5.0 mL) wasstirred under argon at 100° C. for 2 hours. The mixture was cooled,poured into 1 molar hydrochloric acid and extracted with ethyl acetate(×2). The combined extracts were washed with water and brine.Purification by preparative HPLC (acetonitrile-water-0.1% TFA, 20-100%)gave the title compound (300 mg, 65%). 1H NMR (400 MHz, DMSO-d₆) δ ppm10.12 (t, J=5.81 Hz, 1H), 7.79 (s, 1H), 7.71-7.76 (m, 1H), 7.66 (d,J=8.34 Hz, 1H), 7.54 (t. J=7.83 Hz, 1H), 7.32 (d, J=4.29 Hz, 4H),7.23-7.29 (m, 1H), 5.07 (s, 2H), 5.03 (s, 2H), 4.22 (d, J=6.06 Hz, 2H),4.15 (q, J=7.07 Hz, 2H), 1.21 (t, J=7.20 Hz, 3H)

11c)N-{[1-[(3-Cyanophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.EthylN-{[1-[(3-cyanophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate(280 mg, 0.6 mmoles) was dissolved in methanol (5 mL) and treated with 1molar sodium hydroxide solution (4 mL) and stirred for 3 hours. Themixture was acidified and extracted into ethyl acetate. Purification bypreparative HPLC (acetonitrile-water-0.1% TFA, 20-100%) andcrystallization from ethanol-water gave the title compound (50 mg, 20%).1H NMR (400 MHz, DMSO-d₆) δ ppm 13.11 (s, 1H), 10.11 (s, 1H), 7.79 (s,1H), 7.74 (d, J=7.58 Hz, 1H), 7.66 (d, J=8.34 Hz, 1H), 7.55 (t, J=7.71Hz, 1H), 7.29-7.35 (m, 4H), 7.23-7.29 (m, 1H), 5.07 (s, 2H), 5.03 (s,2H), 4.14 (d, J=5.81 Hz, 2H).

Example 12

N-[(6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

A mixture of ethylN-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate(example 11a, 356 mg, 1.03 mmoles), 4-trifluoromethylbenzyl bromide (175uL, 1.13 mmoles) and sodium carbonate (330 mg, 3.1 mmoles) indimethylformamide (6.0 mL) was stirred under argon at 100° C. for 2.5hours. The mixture was cooled, poured into 1 molar hydrochloric acid andextracted with ethyl acetate (×2). The ester was hydrolysed by stirringin a mixture of ethanol (3 mL) and 1 molar sodium hydroxide solution (3mL) for 3 hours. The mixture was acidified and extracted with ethylacetate. Purification by preparative HPLC (acetonitrile-water-0.1% TFA,20-100%) and crystallization from ethanol-water gave the title compound(150 mg, 30%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.12 (s, 1H), 10.12 (t,J=5.56 Hz, 1H), 7.69 (d, J=8.08 Hz, 2H), 7.53 (d, J=8.08 Hz, 2H),7.24-7.35 (m, 5H), 5.11 (s, 2H), 5.03 (s, 2H), 4.14 (d, J=5.81 Hz, 2H).

Example 13

N-{[1-[(3,4-Dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

A mixture of ethylN-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate(example 11a, 357 mg, 1.03 mmoles), 3,4-dichlorobenzyl bromide (193 uL,1.13 mmoles) and sodium carbonate (330 mg, 3.1 mmoles) indimethylformamide (6.0 mL) was stirred under argon at 100° C. for 2.5hours. The mixture was cooled, poured into 1 molar hydrochloric acid andextracted with ethyl acetate (×2). The ester was hydrolysed by stirringin a mixture of ethanol (3 mL) and 1 molar sodium hydroxide solution (3mL) for 3 hours. The mixture was acidified and extracted with ethylacetate. Purification by preparative HPLC (acetonitrile-water-0.1% TFA,20-100%) and crystallization from ethanol-water gave the title compound(50 mg, 10%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.13 (s, 1H), 10.11 (t,J=5.68 Hz, 1H), 7.59 (dd, J=5.18, 3.16 Hz, 2H), 7.24-7.34 (m, 6H), 5.01(s, 2H), 5.02 (s, 2H), 4.14 (d, J=5.81 Hz, 2H).

Example 14

N-{[6-Hydroxy-1-{[3-(methyloxy)phenyl]methyl}-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

A mixture of ethylN-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate(example 11a, 369 mg, 1.06 mmoles), 3-methoxybenzyl bromide (163 uL,1.17 mmoles) and sodium carbonate (330 mg, 3.1 mmoles) indimethylformamide (6.0 mL) was stirred under argon at 100° C. for 2.5hours. The mixture was cooled, poured into 1 molar hydrochloric acid andextracted with ethyl acetate (×2). The ester was hydrolysed by stirringin a mixture of ethanol (3 mL) and 1 molar sodium hydroxide solution (3mL) for 3 hours. The mixture was acidified and extracted with ethylacetate. Purification by preparative HPLC (acetonitrile-water-0.1% TFA,20-100%) and crystallization from ethanol-water gave the title compound(50 mg, 11%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (br. s., 1H), 10.12(t, 1H), 7.14-7.47 (m, 6H), 6.69-6.97 (m, 3H), 5.00 (s, 2H), 5.03 (s,2H), 4.13 (d, J=5.56 Hz, 2H), 3.71 (s, 3H).

Example 15

N-{[1-[(2,6-Dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

A mixture of ethylN-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate(example 11a, 388 mg, 1.12 mmoles), 2,6-dichlorobenzyl bromide (295 uL,1.23 mmoles) and sodium carbonate (330 mg, 3.1 mmoles) indimethylformamide (6.0 mL) was stirred under argon at 100° C. for 2.5hours. The mixture was cooled, poured into 1 molar hydrochloric acid andextracted with ethyl acetate (×2). The ester was hydrolysed by stirringin a mixture of ethanol (3 mL) and 1 molar sodium hydroxide solution (3mL) for 3 hours. The mixture was acidified and extracted with ethylacetate. Purification by preparative HPLC (acetonitrile-water-0.1% TFA,20-100%) and crystallization from ethanol-water gave the title compound(60 mg, 11%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.12 (br. s., 1H), 10.02(br. s., 1H), 7.42 (d, 2H), 7.22-7.35 (m, 6H), 5.30 (s, 2H), 5.01 (s,2H), 4.12 (d, J=5.81 Hz, 2H).

Example 16

N-{[6-Hydroxy-1-methyl-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

A mixture of ethylN-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate(295 mg, 0.85 mmoles), methyl iodide (62 uL, 1.0 mmoles) and sodiumcarbonate (320 mg, 3.0 mmoles) in dimethylformamide (5.0 mL) was stirredunder argon at 100° C. for 2.5 hours. The mixture was cooled, pouredinto 1 molar hydrochloric acid and extracted with ethyl acetate (×2).The ester was hydrolysed by stirring in a mixture of ethanol (5 mL) and1 molar sodium hydroxide solution (4 mL) for 4 hours. The mixture wasacidified and extracted with ethyl acetate. Purification by preparativeHPLC (acetonitrile-water-0.1% TFA, 20-100%) and crystallization fromether-hexane gave the title compound (80 mg, 28%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.11 (br. s., 1H), 10.09 (br. s., 1H), 7.28-7.36 (m,4H), 7.19-7.29 (m, 1H), 5.01 (s, 2H), 4.14 (d, J=5.81 Hz, 2H), 3.21 (s,3H).

Example 17

N-{[1-Cyclohexyl-3-(2-cyclopropylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

17a) N-Cyclohexyl-N′-(2-cyclopropylethyl)urea. Cyclohexyl isocyanate(564 uL, 4.7 mmoles) was added to a solution of cyclopropylethylaminehydrochloride (537 mg, 4.4 mmoles) and triethylamine (615 uL, 4.4mmoles) in chloroform (10 mL) under argon at room temperature. Themixture was stirred for 1 hour, washed with 1 molar hydrochloric acid,dried and evaporated. Trituration with hexane gave a solid (550 mg,59%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.55 (br. s., 1H), 3.47-3.59(m, 1H), 3.27 (t, J=6.95 Hz, 2H), 1.95 (dd, J=12.63, 3.54 Hz, 2H),1.67-1.79 (m, 2H), 1.58-1.67 (m, 1H), 1.43 (q, J=6.99 Hz, 2H), 1.30-1.40(m, 2H), 1.07-1.24 (m, 3H), 0.63-0.77 (m, 1H), 0.44-0.51 (m, 2H),0.05-0.12 (m, 2H)

17b)1-Cyclohexyl-3-(2-cyclopropylethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione.Malonyl dichloride (250 uL, 2.57 mmoles) was added dropwise to asolution of N-cyclohexyl-N-(2-cyclopropylethyl)urea (500 mg, 2.38mmoles) in dichloromethane under argon. The mixture was stirredovernight then heated under reflux for 2 hours. Flash chromatography(hexane to 20% ethyl acetate-hexane) gave the title compound (230 mg,35%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.57-4.71 (m, 1H), 3.94-4.04(m, 2H), 3.60-3.68 (m, 2H), 2.20-2.36 (m, 2H), 1.86 (d, J=13.39 Hz, 2H),1.60-1.73 (m, 3H), 1.45-1.60 (m, 2H), 1.29-1.44 (m, 2H), 1.15-1.29 (m,1H), 0.62-0.77 (m, 1H), 0.40-0.51 (m, 2H), −0.00-0.12 (m, 2H).

17c)N-{[1-cyclohexyl-3-(2-cyclopropylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A solution of1-cyclohexyl-3-(2-cyclopropylethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(225 mg, 0.8 mmoles) and diisopropylethylamine (280 uL, 1.6 mmoles) inchloroform (10 mL) was treated with ethyl 2-isocyanatoacetate (91 uL,0.81 mmoles) and stirred for 1 hour. The mixture was washed withhydrochloric acid (×2) and evaporated. The residue was dissolved inethanol (3 mL) and treated with 1 molar sodium hydroxide solution andstirred for 3 hours. The mixture was partitioned between ethyl acetateand 1 molar hydrochloric acid, separated and the organic solution washedwith brine, dried and evaporated. The solid residue was reprecipitatedfrom ether-hexane to give the title compound (190 mg, 63%). 1H NMR (400MHz, DMSO-d₆) δ ppm 13.07 (br. s, 1H), 10.14 (t, J=5.81 Hz, 1H), 4.64(s, 1H), 4.12 (d, J=5.81 Hz, 2H), 3.87-3.92 (m, 2H), 2.22-2.34 (m, 2H),1.79 (d, J=13.14 Hz, 2H), 1.61 (t, J=12.13 Hz, 3H), 1.45 (q, J=7.16 Hz,2H), 1.23-1.33 (m, 2H), 1.08-1.18 (m, 1H), 0.62-0.70 (m, 1H), 0.35-0.40(m, 2H), −0.04-0.00 (m, 2H)

Example 18

N-[(1,3-Dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Method 1

18.1a) 1,3-Dicyclohexyl-2,4,6(1H,3H,5H)-pyrimidinetrione.Dicyclohexylurea (3.0 g, 13.39 mmoles) was stirred in chloroform (80 mL)and treated with a solution of malonyl dichloride (1.3 mL, 13.39 mmoles)in chloroform (20 mL), added dropwise under argon. The mixture washeated at 50° C. for 4 hours, washed with 1 molar hydrochloric acid andevaporated onto silica gel. Flash chromatography (10-30% ethyl acetatein hexane) to give the title compound (2.13 g, 55%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 4.46 (tt, J=12.13, 3.54 Hz, 2H), 3.69 (s, 2H), 2.15 (qd,J=12.46, 3.28 Hz, 4H), 1.77 (d, J=13.14 Hz, 4H), 1.59 (t, J=12.76 Hz,6H), 1.26 (q, J=12.97 Hz, 4H), 1.04-1.16 (m, 2H)

18.1b)N-[(1,3-Dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.Ethyl isocyanatoacetate (802 uL, 7.15 mmoles) was added to a mixture of1,3-dicyclohexyl-2,4,6(1H,3H,5H)-pyrimidinetrione (2.1 g, 7.15 mmoles)and diisopropylethylamine (2.47 mL, 14.3 mmoles) in dichloromethane (100mL) and stirred overnight. The reaction mixture was washed with 1 molarhydrochloric acid (×2) and evaporated. The residue was dissolved inethanol (10 mL) and treated with 1.0 molar sodium hydroxide (5 mL). Themixture was stirred for 72 hours, acidified and extracted into ethylacetate. Some ester remained, therefore the solution was evaporated andthe residue was dissolved in 1 molar sodium hydroxide solution withwarming and stirred for 2 hours. The mixture was acidified with 1M HCland extracted with ethyl acetate (×2). The combined extracts were washedwith 1 molar hydrochloric acid, dried and evaporated to a solid whichwas slurried in a mixture of diethyl ether and hexane, collected, washedwith the same solvent mixture and dried to give the title compound (1.86g, 66%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.07 (br. s., 1H), 10.19 (t,J=5.31 Hz, 1H), 4.63 (t, J=10.99 Hz, 2H), 4.12 (d, J=5.56 Hz, 2H), 2.27(q, J=11.71 Hz, 4H), 1.79 (d, J=12.88 Hz, 4H), 1.50-1.69 (m, 6H), 1.28(q, J=12.97 Hz, 4H), 1.12 (q, J=12.72 Hz, 2H)

Method 2

18.2a) 1,3-Dicyclohexyl-2,4,6(1H,3H,5H)-pyrimidinetrione. A solution ofN,N-dicyclohexylcarbodiimide (254 g; 1.23 mol.) in anhydrous THF (700mL) was added dropwise to a cold (0° C.) solution of malonic acid (64.1g; 0.616 mol.) in anhydrous THF (300 mL) over a period of ˜30 minutes.The mixture was stirred and allowed to warm to room temperature over 2h. (After 1 h, the mixture became very thick with precipitate so furtheranhydrous THF (500 mL) was added to facilitate agitation.). The mixturewas filtered and the filtrate evaporated to afford a yellow solid whichwas immediately slurried in ethanol (1 L) and heated to refluxtemperature. The mixture was then allowed to cool to room temperaturethen filtered and the solid washed with cold ethanol (250 mL) to affordthe title compound (129.4 g; 72%) as a colorless solid. 1H NMR (400 MHz,DMSO-d₆) δ ppm 1.03-1.18 (m, 2H) 1.18-1.34 (m, 4H) 1.59 (t, J=13.14 Hz,6H) 1.76 (d, J=12.88 Hz, 4H) 2.04-2.24 (m, 4H) 3.69 (s, 2H) 4.35-4.54(m, 2H).

18.2b) EthylN-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate.A solution of 1,3-dicyclohexyl-2,4,6(1H,3H,5H)-pyrimidinetrione (120.0g; 0.41 mol.) and diisopropylethylamine (105.8 g; 0.82 mol.) indichloromethane (1 L) was stirred and treated dropwise with a solutionof ethyl isocyanatoacetate (53.0 g; 0.41 mol.) in dichloromethane (500mL) and the mixture was then stirred at room temperature overnight. Themixture was then treated dropwise with 6M aq. hydrochloric acid (500 mL)and the separated organic layer was dried and evaporated. The resultingsolid was slurried in hexanes (500 mL) and heated to reflux temperature.The mixture was then allowed to cool and filtered to afford ethylN-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(159.1 g; 92%) as a cream powder. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm1.24 (s, 2H) 1.37 (s, 7H) 1.52-1.76 (m, 6H) 1.78-1.94 (m, 4H) 2.25-2.48(m, 4H) 4.17 (d, J=5.81 Hz, 2H) 4.28 (q, J=7.24 Hz, 2H) 4.74 (s, 2H)10.37 (t, J=4.67 Hz, 1H).

18.2c)N-[(1,3-Dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.A stirred suspension of ethylN-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(159.0 g; 0.377 mol.) in ethanol (1.5 L) was treated dropwise with 6Maq. Sodium hydroxide (250 mL) and stirred at room temperature for 3 h.The solution was then acidified by the dropwise addition of 6M aq.hydrochloric acid (300 mL), diluted with water (1 L) and then filtered.The crude solid was slurried in water (2 L) then stirred vigorously andheated at 35° C. for 1 h and filtered and dried. The solid material (˜138 g) was then crystallized from glacial acetic acid (1.5 L) (with hotfiltration to remove a small amount of insoluble material). The solid,which crystallized upon cooling, was collected and washed with coldglacial acetic acid (3×100 mL) to affordN-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine(116.2 g; 78%) as a colorless solid. 1H NMR (400 MHz, DMSO-d₆) δ ppm1.11 (d, J=12.88 Hz, 2H) 1.27 (q, J=12.80 Hz, 4H) 1.62 (s, 6H) 1.70-1.90(m, J=12.88 Hz, 4H) 2.11-2.44 (m, 4H) 4.11 (d, J=5.81 Hz, 2H) 4.45-4.77(m, 2H) 10.19 (t, J=5.81 Hz, 1H) 13.08 (s, 1H).

Example 19

N-{[1-Hexyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

19a) N-Hexyl-N′-(phenylmethyl)urea. n-Hexyl isocyanate (620 uL, 4.24mmoles) was added to a solution of benzylamine hydrochloride (610 mg,4.24 mmoles) and diisopropylethylamine (735 uL, 4.24 mmoles) inchloroform (10 mL). The mixture was stirred for 1 hour, washed with 1molar hydrochloric acid (×2), dried and evaporated to give the titlecompound (993 mg, 91%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18-7.45(m, 5H), 4.37 (s, 2H), 3.15 (t, J=7.20 Hz, 2H), 1.42-1.53 (m, 2H),1.23-1.36 (m, 6H), 0.84-0.94 (m, 3H).

19b) 1-Hexyl-3-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione. Malonyldichloride (411 uL, 4.2 mmoles) was added to a solution ofN-hexyl-M-(phenylmethyl)urea (900 mg, 3.8 mmoles) in dichloromethane (25mL) and the mixture was heated under reflux for 3 hours. The mixture waswashed with 1 molar hydrochloric acid and evaporated. Flashchromatography (10-15% ethyl acetate in hexane) gave the title compound(480 mg, 42%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.46 (dd, J=7.83,1.52 Hz, 2H), 7.28-7.41 (m, 3H), 5.07 (s, 2H), 3.82-3.91 (m, 2H), 3.70(s, 2H), 1.52-1.66 (m, 2H), 1.19-1.38 (m, 6H), 0.79-0.97 (m, 3H).

19c)N-{[1-Hexyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of 1-hexyl-3-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(470 mg, 1.55 mmoles), diisopropylethylamine (280 uL, 1.6 mmoles) andethyl 2-isocyanatoacetate (132 uL, 1.55 mmoles) was stirred inchloroform (10 mL) for 3 hours. The mixture was washed with hydrochloricacid (×2) and evaporated. The residue was dissolved in ethanol (15 mL),treated with 1 molar sodium hydroxide solution and stirred for 4 hours.The mixture was partitioned between ethyl acetate and 1 molarhydrochloric acid. The aqueous was extracted with ethyl acetate and thecombined extracts washed with 1 molar hydrochloric acid and brine, driedand evaporated. A solid was obtained from diethyl ether-hexane andrecrystallized from toluene-hexane to give the title compound (280 mg,46%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.11 (s, 1H), 10.10 (s, 1H),7.24-7.34 (m, 5H), 5.01 (s, 2H), 4.13 (d, J=5.81 Hz, 2H), 3.77-3.86 (m,2H), 1.54 (d, J=6.82 Hz, 2H), 1.26 (s, 6H), 0.81-0.89 (m, 3H).

Example 20

N-{[1-Ethyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

20a) 1-Ethyl-3-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione. Malonyldichloride (411 uL, 4.2 mmoles) was added to a solution ofN-ethyl-M-(phenylmethyl)urea (685 mg, 3.84 mmoles) in dichloromethane(25 mL) and the mixture was heated under reflux for 1 hour. The mixturewas washed with 1 molar hydrochloric acid and evaporated. Flashchromatography (10-30% ethyl acetate in hexane) gave the title compound(390 mg, 42%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.41-7.49 (m, 2H),7.25-7.34 (m, 3H), 5.03 (s, 2H), 3.92 (q, J=7.07 Hz, 2H), 3.64 (s, 2H),1.20 (t, J=7.07 Hz, 3H).

20b)N-{[1-Ethyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A solution of 1-ethyl-3-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(390 mg, 1.58 mmoles) and diisopropylethylamine (546 uL, 3.16 mmoles) inchloroform (10 mL) was treated with ethyl isocyanatoacetate (135 uL,1.58 mmoles) and stirred for 2 hours under argon. The mixture was washedwith 1 molar hydrochloric acid (×2), dried and evaporated. The residuewas dissolved in ethanol (10 mL), treated with 1 molar sodium hydroxidesolution (5 mL) and stirred overnight. The mixture was acidified andextracted into ethyl acetate and the organic solution dried andevaporated. Crystallization from methanol-water gave the title compound(350 mg, 64%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.12 (br. s, 1H), 10.10(s, 1H), 7.24-7.35 (m, 5H), 5.01 (s, 2H), 4.14 (d, J=5.56 Hz, 2H), 3.87(q, J=6.99 Hz, 2H), 1.14 (t, J=6.95 Hz, 3H).

Example 21

N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-propyl-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

21a) 1-(Phenylmethyl)-3-propyl-2,4,6(1H,3H,5H)-pyrimidinetrione. Malonyldichloride (427 uL, 4.4 mmoles) was added to a solution ofN-(phenylmethyl)-N′-propylurea (778 mg, 4.04 mmoles) in dichloromethane(25 mL) and the mixture was heated under reflux for 1 hour. The mixturewas washed with 1 molar hydrochloric acid and evaporated. Flashchromatography (10-20% ethyl acetate in hexane) gave the title compound(730 mg, 70%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.46 (dd, J=8.08,1.52 Hz, 2H), 7.29-7.38 (m, 3H), 5.07 (s, 2H), 3.79-3.87 (m, 2H), 3.69(s, 2H), 1.57-1.69 (m, 2H), 0.94 (t, J=7.45 Hz, 3H)

21b)N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-propyl-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A solution of 1-(phenylmethyl)-3-propyl-2,4,6(1H,3H,5H)-pyrimidinetrione(730 mg, 2.8 mmoles) and diisopropylethylamine (970 uL, 5.6 mmoles) inchloroform (12 mL) was treated with ethyl isocyanatoacetate (239 uL, 2.8mmoles) and stirred for 2 hours under argon. The mixture was washed with1 molar hydrochloric acid (×2), dried and evaporated. The residue wasdissolved in ethanol (10 mL), treated with 1 molar sodium hydroxidesolution (5 mL) and stirred overnight. The mixture was acidified andextracted into ethyl acetate and the organic solution dried andevaporated. Crystallization from ethanol-water gave the title compound(800 mg, 71%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.11 (s, 1H), 10.11 (s,1H), 7.24-7.34 (m, 5H), 5.01 (s, 2H), 4.13 (d, J=5.81 Hz, 2H), 3.75-3.84(m, 2H), 1.52-1.63 (m, 2H), 0.86 (t, J=7.45 Hz, 3H)

Example 22

N-{[1-Butyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

22a) 1-Butyl-3-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione. Malonyldichloride (497 uL, 5.1 mmoles) was added to a solution ofN-butyl-N-(phenylmethyl)urea (959 mg, 4.65 mmoles) in dichloromethane(25 mL) and the mixture was heated under reflux for 1 hour. The mixturewas washed with 1 molar hydrochloric acid and evaporated. Flashchromatography (0-15% ethyl acetate in hexane) gave the title compound(676 mg, 53%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.29-7.35 (m, 4H),7.20-7.28 (m, 1H), 4.92 (s, 2H), 3.82 (s, 2H), 3.71 (t, 2H), 1.48 (tt,2H), 1.28 (tq, J=7.49, 7.33 Hz, 2H), 0.88 (t, J=7.33 Hz, 3H).

22b)N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-propyl-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A solution of 1-butyl-3-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(676 mg, 2.46 mmoles) and diisopropylethylamine (826 uL, 4.93 mmoles) inchloroform (12 mL) was treated with ethyl isocyanatoacetate (211 uL,2.46 mmoles) and stirred for 3 hours under argon. The mixture was washedwith 1 molar hydrochloric acid (×2), dried and evaporated. The residuewas dissolved in ethanol (10 mL), treated with 1 molar sodium hydroxidesolution (7 mL) and stirred overnight. The mixture was acidified andextracted into ethyl acetate and the organic solution dried andevaporated. Crystallization from ethanol-water gave the title compound(580 mg, 63%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (s, 1H), 10.11 (s,1H), 7.24-7.35 (m, 5H), 5.01 (s, 2H), 4.13 (d, J=5.81 Hz, 2H), 3.79-3.87(m, 2H), 1.54 (dq, J=7.58, 7.41 Hz, 2H), 1.29 (dq, J=14.97, 7.39 Hz,2H), 0.89 (t, J=7.45 Hz, 3H).

Example 23

N-{[6-Hydroxy-2,4-dioxo-1-(2-phenylethyl)-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

23a) N-(2-Phenylethyl)-N-(phenylmethyl)urea. Phenethyl isocyanate (612uL, 4.42 mmoles) was added to a stirred solution of benzylaminehydrochloride (635 mg, 4.42 mmoles) and diisopropylamine (766 uL, 4.42mmoles) in chloroform under argon and stirred for 1 hour. The mixturewas washed with 1 molar hydrochloric acid (×2), dried and evaporated togive the title compound (1.0 g, 89%). 1H NMR (400 MHz, CHLOROFORM-d) δppm 7.20-7.41 (m, 8H), 7.18 (d, J=6.82 Hz, 2H), 4.34 (s, 1H), 3.47 (t,J=6.82 Hz, 2H), 2.82 (t, J=6.95 Hz, 2H).

23b)1-(2-Phenylethyl)-3-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione.Malonyl dichloride (546 uL, 5.6 mmoles) was added to a solution ofN-(2-phenylethyl)-N-(phenylmethyl)urea (1.0 g, 3.93 mmoles) indichloromethane (25 mL) and the mixture was heated under reflux for 1hour. The mixture was washed with 1 molar hydrochloric acid andevaporated. Flash chromatography (10-25% ethyl acetate in hexane) gavethe title compound (930 mg, 73%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.43 (dd, J=7.96, 1.64 Hz, 2H), 7.14-7.40 (m, 8H), 5.06 (s, 2H),4.08-4.17 (m, 2H), 3.64 (s, 2H), 2.87-2.97 (m, 2H)

23c)N-{[6-Hydroxy-2,4-dioxo-1-(2-phenylethyl)-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A solution of1-(2-phenylethyl)-3-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (930mg, 2.89 mmoles) and diisopropylethylamine (1.0 mL, 5.78 mmoles) inchloroform (15 mL) was treated with ethyl isocyanatoacetate (250 uL,2.89 mmoles) and stirred for 3 hours under argon. The mixture was washedwith 1 molar hydrochloric acid (×2), dried and evaporated. The residuewas dissolved in ethanol (10 mL), treated with 1 molar sodium hydroxidesolution (10 mL) and stirred overnight. The mixture was acidified andextracted into ethyl acetate and the organic solution dried andevaporated to a solid. The solid was slurried in diethyl ether,collected, washed with diethyl ether and hexane and dried to afford thetitle compound (580 mg, 47%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.11 (br.s., 1H), 10.10 (br. s., 1H), 7.08-7.44 (m, 10H), 5.00 (s, 2H), 4.14 (d,J=5.81 Hz, 2H), 3.98-4.10 (m, 2H), 2.87 (t, 2H)

Example 24

N-{[3-{[4-(1,1-Dimethylethyl)phenyl]methyl}-6-hydroxy-1-(1-methylethyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

24a)1-{[4-(1,1-Dimethylethyl)phenyl]methyl}-3-(1-methylethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione.A mixture of 4-t-butylbenzylamine (704 uL, 4.0 mmoles) and isopropylisocyanate (392 uL, 4.0 mmoles) was stirred in chloroform (10 mL) for 1hour. Malonyl dichloride (388 uL, 4.0 mmoles) was added and the mixturewas heated at 45° C. for 1 hour. The mixture was washed with 1 molarhydrochloric acid and purified by flash chromatography (10-25% ethylacetate-hexane) to give the title compound (385 mg, 30%). 1H NMR (400MHz, CHLOROFORM-d) δ ppm 7.34-7.43 (m, 4H), 5.03-5.09 (m, 1H), 5.03 (s,2H), 3.66 (s, 2H), 1.45 (d, J=7.07 Hz, 6H), 1.32 (s, 9H).

24b)N-{[3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-1-(1-methylethyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A solution of1-{[4-(1,1-dimethylethyl)phenyl]methyl}-3-(1-methylethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(385 mg, 1.21 mmoles) and diisopropylethylamine (418 uL, 2.42 mmoles) inchloroform (10 mL) was treated with ethyl isocyanatoacetate (103 uL,1.21 mmoles) and stirred for 3 hours under argon. The mixture was washedwith 1 molar hydrochloric acid (×2), dried and evaporated. The residuewas dissolved in ethanol (5 mL), treated with 1 molar sodium hydroxidesolution (8 mL) and stirred for 3 hours. The mixture was acidified andextracted into ethyl acetate and the organic solution dried andevaporated. A solid was obtained by trituration in hexane plus a littlediethyl ether, collected, washed with hexane to give the title compound(338 mg, 67%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.09 (br.s, 1H), 10.12(br.s, 1H), 7.34 (d, J=8.34 Hz, 2H), 7.22 (d, J=8.59 Hz, 2H), 5.06 (ddd,J=13.52, 6.69, 6.57 Hz, 1H), 4.96 (s, 2H), 4.13 (d, J=5.81 Hz, 2H), 1.41(d, J=7.07 Hz, 6H), 1.25 (s, 9H)

Example 25

N-[(1-cyclohexyl-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

25a)1-Cyclohexyl-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione.A mixture of 4-t-butylbenzylamine (880 uL, 5.0 mmoles) and cyclohexylisocyanate (638 uL, 5.0 mmoles) was stirred in dichloromethane (40 mL)for 1 hour. Malonyl dichloride (388 uL, 4.0 mmoles) was added and themixture was heated under gentle reflux for 1 hour. The mixture waswashed with 1 molar hydrochloric acid and purified by flashchromatography (10-25% ethyl acetate-hexane) to give the title compound(1.23 g, 69%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.33-7.43 (m, 4H),5.02 (s, 2H), 4.56-4.70 (m, 1H), 3.65 (s, 2H), 2.20-2.35 (m, 2H), 1.85(d, J=13.39 Hz, 2H), 1.65 (t, J=16.42 Hz, 3H), 1.20-1.43 (m, 11H)

25b)N-[(1-Cyclohexyl-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.A solution1-cyclohexyl-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione(1.23 g, 3.45 mmoles) and diisopropylethylamine (1.2 mL, 6.9 mmoles) inchloroform (20 mL) was treated with ethyl isocyanatoacetate (295 uL,3.45 mmoles) and stirred overnight under argon. The mixture was washedwith 1 molar hydrochloric acid (×2), dried and evaporated. The residuewas dissolved in ethanol (8 mL), treated with 1 molar sodium hydroxidesolution (8 mL) and stirred for 3 hours. The mixture was diluted withethyl acetate, washed with 1 molar hydrochloric acid (×2), dried andevaporated. A solid was obtained from ethanol-water to give the titlecompound (1.3 g, 82%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (br. s.,1H), 10.14 (br. s., 1H), 7.34 (d, J=8.34 Hz, 2H), 7.22 (d, J=8.34 Hz,2H), 4.95 (s, 2H), 4.65 (t, J=11.75 Hz, 1H), 4.13 (d, J=5.81 Hz, 2H),2.14-2.37 (m, 2H), 1.79 (d, J=12.63 Hz, 2H), 1.62 (d, J=11.62 Hz, 3H),1.19-1.37 (m, 11H), 1.04-1.19 (m, 1H)

Example 26

N-{[6-Hydroxy-1,3-bis(1-methylethyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

26a) 1,3-Bis(1-methylethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione. A solutionof isopropylamine (520 uL, 6.11 mmoles) was stirred in dichloromethane(25 mL) under nitrogen, treated with isopropyl isocyanate (600 uL, 6.11mmoles) in dichloromethane (25 mL) and stirred for 1 hour. Malonyldichloride (593 uL, 6.11 mmoles) was added and the mixture was heatedunder gentle reflux for 1 hour. The mixture was washed with 1 molarhydrochloric acid and purified by flash chromatography (10-30% ethylacetate-hexane) to give the title compound (900 mg, 69%). 1H NMR (400MHz, CHLOROFORM-d) δ ppm 5.04 (dt, J=13.89, 6.95 Hz, 2H), 3.61 (s, 2H),1.45 (d, J=7.07 Hz, 12H).

26b)N-{[6-Hydroxy-1,3-bis(1-methylethyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A solution 1,3-bis(1-methylethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (900mg, 4.24 mmoles) and diisopropylethylamine (1.47 mL, 8.48 mmoles) inchloroform (15 mL) was treated with ethyl isocyanatoacetate (362 uL,4.24 mmoles) and stirred for 4 hours under nitrogen. The mixture waswashed with 1 molar hydrochloric acid (×2), dried and evaporated. Theresidue was dissolved in ethanol (6 mL), treated with 1 molar sodiumhydroxide solution (8 mL) and stirred overnight. The mixture was dilutedwith ethyl acetate, washed with 1 molar hydrochloric acid (×2), driedand evaporated to a solid that crystallized from diethyl ether-hexane togive the title compound (925 mg, 69%). 1H NMR (400 MHz, DMSO-d₆) δ ppm13.06 (s, 1H), 10.14 (t, J=5.81 Hz, 1H), 4.98-5.09 (m, 2H), 4.12 (d,J=5.81 Hz, 2H), 1.39 (d, J=6.82 Hz, 12H)

Example 27

N-{[3-[(2-Bromophenyl)methyl]-1-(1,1-dimethylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

27a)1-[(2-Bromophenyl)methyl]-3-(1,1-dimethylethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione.t-Butyl isocyanate (571 uL, 5.0 mmoles) was added to a solution of2-bromobenzylamine hydrochloride (1.112 g, 5.0 mmoles) anddiisopropylethylamine (864 uL, 5.0 mmoles) in chloroform (50 mL) and themixture stirred for 1 hour. Malonyl dichloride (486 uL, 5.0 mmoles) wasadded and the mixture was stirred at 50° C. for 1 hour. The mixture waswashed with 1 molar hydrochloric acid and evaporated. Flashchromatography (10-35% ethyl acetate-hexane) afforded the title compound(500 mg, 28%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.59 (dd, J=8.08,1.26 Hz, 1H), 7.26-7.32 (m, 1H), 7.12-7.19 (m, 1H), 6.99 (dd, J=7.58,1.52 Hz, 1H), 5.12 (s, 2H), 3.72 (s, 2H), 1.63 (s, 9H)

27b)N-{[3-[(2-Bromophenyl)methyl]-1-(1,1-dimethylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.1-[(2-Bromophenyl)methyl]-3-(1,1-dimethylethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(500 mg, 1.41 mmoles) and diisopropylethylamine (490 uL, 2.82 mmoles)were stirred together in dry chloroform (15 mL) and treated with ethylisocyanatoacetate (121 uL, 1.41 mmoles). The mixture was stirred for 3hours, washed twice with 1 molar hydrochloric acid, dried andevaporated. The residue was dissolved in ethanol (5.0 mL) and treatedwith 1 molar sodium hydroxide solution (6.0 mL)) and stirred overnight.The mixture was partitioned between ethyl acetate and 1 molarhydrochloric acid, the organic solution washed with 1 molar hydrochloricacid, dried and evaporated. The title compound was obtained bycrystallization from ethanol-water (390 mg, 61%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.08 (s, 1H), 10.05 (s, 1H), 7.65 (dd, J=8.08, 1.01 Hz,1H), 7.34 (t, J=6.95 Hz, 1H), 7.22 (td, J=7.71, 1.52 Hz, 1H), 7.03 (d,J=6.57 Hz, 1H), 4.96 (s, 2H), 4.12 (d, J=5.81 Hz, 2H), 1.66 (s, 9H).

Example 28

N-[(1-(2,6-Dichlorophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

28a)1-(2,6-Dichlorophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione.A mixture of 2,6-dichlorophenlisocyanate (1.47 g, 7.82 mmoles) and4-t-butylbenzylamine (1.38 g, 7.82 mmoles) in dichloromethane (100 mL)was stirred under argon for 1 hour. Malonyl dichloride (760 uL, 7.82mmoles) was added and the mixture was heated at 40° C. for 1 hour. Themixture was washed with 1 molar hydrochloric acid and evaporated. Flashchromatography (10-25% ethyl acetate-hexane) afforded the title compound(2.2 g, 67%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50 (d, J=1.26 Hz,1H), 7.48 (d, J=0.51 Hz, 2H), 7.35-7.41 (m, 5H), 5.11 (s, 2H), 3.92 (s,2H), 1.33 (s, 9H).

28b)N-[(1-(2,6-Dichlorophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.1-(2,6-Dichlorophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione(2.3 g, 5.48 mmoles) and diisopropylethylamine (1.9 mL, 10.97 mmoles)were stirred together in dry chloroform (50 mL) and treated with ethylisocyanatoacetate (469 uL, 5.48 mmoles). The mixture was stirredovernight, washed twice with 1 molar hydrochloric acid, dried andevaporated. Flash chromatography (dichloromethane) gave pure ester whichwas dissolved in ethanol (10 mL) and treated with 6 molar sodiumhydroxide solution (5.0 mL)) and stirred overnight. The mixture waspartitioned between ethyl acetate and 1 molar hydrochloric acid, theorganic solution washed with 1 molar hydrochloric acid, dried andevaporated. The title compound was obtained by crystallization fromethanol-water (1.8 g, 63%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.20 (s,1H), 10.08 (s, 1H), 7.67-7.74 (m, 2H), 7.54-7.61 (m, 1H), 7.37 (d,J=8.34 Hz, 2H), 7.22 (d, J=8.59 Hz, 2H), 5.06 (s, 2H), 4.15 (d, J=5.56Hz, 2H), 1.26 (s, 9H).

Example 29

N-[(1-(2,4-dichlorophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

29a)1-(2,4-Dichlorophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione.A mixture of 2,4-dichlorophenlisocyanate (1.43 g, 7.6 mmoles) and4-t-butylbenzylamine (1.34 ml, 7.6 mmoles) in dichloromethane (100 mL)was stirred under argon for 1 hour. Malonyl dichloride (739 uL, 7.6mmoles) was added and the mixture was heated at 40° C. for 1 hour. Themixture was washed with 1 molar hydrochloric acid and evaporated. Flashchromatography (10-25% ethyl acetate-hexane) afforded the title compound(2.6 g, 82%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=2.27 Hz,1H), 7.35-7.43 (m, 5H), 7.21 (d, J=8.59 Hz, 1H), 5.10-5.17 (m, 1H),5.01-5.07 (m, 1H), 3.89 (d, J=5.81 Hz, 2H), 1.33 (s, 9H)

29b)N-[(1-(2,4-Dichlorophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.1-(2,4-Dichlorophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione(2.57 g, 6.13 mmoles) and diisopropylethylamine (2.12 mL, 12.26 mmoles)were stirred together in dry chloroform (50 mL) and treated with ethylisocyanatoacetate (524 uL, 6.13 mmoles). The mixture was stirredovernight, washed twice with 1 molar hydrochloric acid, dried andevaporated. Flash chromatography (dichloromethane) gave pure ester whichwas dissolved in ethanol (10 mL) and treated with 6 molar sodiumhydroxide solution (5.0 mL)) and stirred overnight. The mixture waspartitioned between ethyl acetate and 1 molar hydrochloric acid, theorganic solution washed with 1 molar hydrochloric acid, dried andevaporated. The title compound was obtained as a solid by triturationwith hexane (680 mg, 51%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.87 (d,J=2.27 Hz, 1H), 7.56-7.68 (m, 2H), 7.62 (none, 2H), 7.36 (d, 2H), 7.26(d, J=8.59 Hz, 2H), 5.02 (d, J=2.27 Hz, 2H), 4.15 (d, J=5.81 Hz, 2H),1.26 (s, 9H).

Example 30

N-[(1-(2-Bromophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

30a)1-(2-Bromophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione.A mixture of 2-bromophenylisocyanate (1.11 g, 5.6 mmoles) and4-t-butylbenzylamine (1.0 ml, 5.6 mmoles) in dichloromethane (100 mL)was stirred under argon for 2 hours. Malonyl dichloride (739 uL, 7.6mmoles) was added and the mixture was heated at 40° C. for 3 hour. Themixture was washed with 1 molar hydrochloric acid and evaporated. Flashchromatography (10-35% ethyl acetate-hexane) afforded the title compound(1.75 g, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.74 (dd, J=7.96,1.39 Hz, 1H), 7.47 (td, J=7.71, 1.52 Hz, 1H), 7.41-7.44 (m, 2H),7.35-7.40 (m, 3H), 7.28 (dd, J=7.83, 1.77 Hz, 1H), 5.11-5.18 (m, 1H),5.02-5.09 (m, 1H), 3.90 (d, J=6.57 Hz, 2H), 1.33 (s, 9H)

30b)N-[(1-(2-Bromophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.1-(2-Bromophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione(1.7 g, 3.96 mmoles) and diisopropylethylamine (1.37 mL, 7.92 mmoles)were stirred together in dry dichloromethane (20 mL) and treated withethyl isocyanatoacetate (338 uL, 3.96 mmoles). The mixture was stirredfor 4 hours, washed twice with 1 molar hydrochloric acid, dried andevaporated. The residue was dissolved in ethanol (10 mL) and treatedwith 1 molar sodium hydroxide solution (6.0 mL) and stirred overnight.The mixture was partitioned between ethyl acetate and 1 molarhydrochloric acid, the organic solution washed with 1 molar hydrochloricacid, dried and evaporated to a foam. The title compound was obtained asa solid by trituration with hexane and standing overnight (1.3 mg, 62%).1H NMR (400 MHz, DMSO-d₆) δ ppm 13.14 (s, 1H), 10.09 (s, 1H), 7.80 (dd,J=8.08, 1.26 Hz, 1H), 7.55-7.61 (m, 1H), 7.53 (td, J=7.58, 1.26 Hz, 1H),7.43 (td, J=7.58, 1.77 Hz, 1H), 7.33-7.40 (m, 2H), 7.24-7.31 (m, 2H),4.98-5.08 (m, 2H), 4.15 (d, J=5.81 Hz, 2H), 1.26 (s, 9H).

Example 31

N-[(1-(2-Biphenylyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

31a)1-(2-Biphenylyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione.A mixture of 2-biphenylisocyanate (858 uL, 5.0 mmoles) and4-t-butylbenzylamine (881 uL, 5.0 mmoles) in dichloromethane (50 mL) wasstirred under argon overnight. Malonyl dichloride (486 uL, 5.0 mmoles)was added and the mixture was heated at 40° C. for 3 hours. The mixturewas washed with 1 molar hydrochloric acid and evaporated. Flashchromatography (10-35% ethyl acetate-hexane) afforded the title compoundas a gum (1.86 g, 87%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.48-7.57 (m,2H), 7.44 (dd, J=7.07, 2.02 Hz, 1H), 7.30-7.41 (m, 4H), 7.26 (d, J=8.34Hz, 2H), 7.13 (d, J=6.82 Hz, 2H), 6.89 (d, J=8.08 Hz, 2H), 4.74-4.85 (m,2H), 3.92 (s, 2H), 1.28 (s, 9H).

31b)N-[(1-(2-Biphenylyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.1-(2-Biphenylyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione(1.8 g, 4.22 mmoles) and diisopropylethylamine (730 uL, 4.22 mmoles)were stirred together in dry dichloromethane (50 mL) and treated withethyl isocyanatoacetate (474 uL, 4.22 mmoles). The mixture was stirredfor under argon overnight, washed twice with 1 molar hydrochloric acid,dried and evaporated. The residue was dissolved in ethanol (10 mL) andtreated with 1 molar sodium hydroxide solution (1.0 mL) and 6 molarsodium hydroxide solution (2.0 mL) and stirred for 24 hours. The mixturewas partitioned between ethyl acetate and 1 molar hydrochloric acid, theorganic solution washed with 1 molar hydrochloric acid, dried andevaporated. The title compound was obtained as a solid by triturationwith a small amount of dichloromethane in hexane (1.3 mg, 58%). 1H NMR(400 MHz, DMSO-d₆) δ ppm 13.09 (br. s, 1H), 10.01 (t, J=5.68 Hz, 1H),7.49-7.58 (m, 2H), 7.41-7.47 (m, 1H), 7.26-7.37 (m, 5H), 7.15 (d, J=6.57Hz, 2H), 6.89 (d, J=8.08 Hz, 2H), 4.89 (s, 2H), 4.11 (d, J=5.81 Hz, 2H),1.28 (s, 9H).

Example 32

N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

32a) 1-(Phenylmethyl)-3-(tetrahydro-2H-pyran-4-yl)-2,4,6(1H,3H,5H)pyrimidinetrione. A mixture of tetrahydro-2H-pyran-4-ylamine (400 mg,3.96 mmoles) and benzyl isocyanate (490 uL, 3.96 mmoles) in chloroform(40 mL) was stirred under inert atmosphere for 4 hours. Malonyldichloride (388 uL, 4.0 mmoles) was added and the mixture was heated at50° C. for 3 hours. The mixture was washed with 1 molar hydrochloricacid and evaporated. Flash chromatography (10-40% ethyl acetate-hexane)afforded the title (980 mg, 82%). 1H NMR (400 MHz, DMSO-d₆) δ ppm7.23-7.35 (m, 5H), 4.91 (s, 2H), 4.69-4.79 (m, J=12.06, 12.06, 3.92,3.79 Hz, 1H), 3.91 (dd, J=11.12, 4.29 Hz, 2H), 3.82 (s, 2H), 3.33 (t,J=11.12 Hz, 2H), 2.41 (qd, J=12.38, 4.55 Hz, 2H), 1.49 (dd, J=12.00,2.15 Hz, 2H).

32b)N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.1-(Phenylmethyl)-3-(tetrahydro-2H-pyran-4-yl)-2,4,6(1H,3H,5H)pyrimidinetrione (970 mg, 3.21 mmoles) and diisopropylethylamine (1.11mL, 6.42 mmoles) were stirred together in dry dichloromethane (50 mL)and treated with ethyl isocyanatoacetate (360 uL, 3.21 mmoles). Themixture was stirred for under argon overnight, washed twice with 1 molarhydrochloric acid, dried and evaporated. The residue was dissolved inethanol (15 mL) and treated with 1 molar sodium hydroxide solution (2.0mL) and 6 molar sodium hydroxide solution (2.0 mL) and stirred for 4hours. The mixture was partitioned between ethyl acetate and 1 molarhydrochloric acid, the organic solution washed with 1 molar hydrochloricacid, dried and evaporated to a solid. The solid was triturated withdiethyl ether, collected, washed with a small amount of diethyl etherand hexane to afford the title compound (1.05 g, 81%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.11 (br. s, 1H), 10.15 (t, J=4.93 Hz, 1H), 7.24-7.35(m, 5H), 5.00 (s, 2H), 4.86-4.96 (m, J=11.91, 11.91, 3.85, 3.66 Hz, 1H),4.14 (d, J=5.81 Hz, 2H), 3.93 (dd, J=11.12, 4.04 Hz, 2H), 3.37 (d,J=11.37 Hz, 2H), 3.32 (s, 1H), 2.53-2.59 (m, 1H), 1.55 (d, J=10.36 Hz,2H).

Example 33

N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

33a)1-Cyclohexyl-3-(tetrahydro-2H-pyran-4-yl)-2,4,6(1H,3H,5H)-pyrimidinetrione.A mixture of tetrahydro-2H-pyran-4-ylamine (400 mg, 3.96 mmoles) andcyclohexyl isocyanate (505 uL, 3.96 mmoles) in chloroform (40 mL) wasstirred under inert atmosphere for 4 hours. Malonyl dichloride (388 uL,4.0 mmoles) was added and the mixture was heated at 50° C. for 3 hours.The mixture was washed with 1 molar hydrochloric acid and evaporated.Flash chromatography (10-35% ethyl acetate-hexane) afforded the title(900 mg, 77%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 4.72 (tt, J=12.09, 3.95Hz, 1H), 4.42-4.51 (m, J=12.16, 12.16, 3.60, 3.41 Hz, 1H), 3.91 (dd,J=11.12, 4.29 Hz, 2H), 3.70 (s, 2H), 3.33 (t, J=10.99 Hz, 3H), 2.42 (qd,J=12.38, 4.80 Hz, 2H), 2.15 (qd, J=12.51, 3.41 Hz, 2H), 1.77 (d, J=13.14Hz, 2H), 1.55-1.65 (m, 3H), 1.48 (dd, J=11.87, 2.27 Hz, 2H), 1.21-1.32(m, 2H), 1.12 (tt, J=12.85, 3.06 Hz, 1H).

33b)N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.1-Cyclohexyl-3-(tetrahydro-2H-pyran-4-yl)-2,4,6(1H,3H,5H)-pyrimidinetrione(900 mg, 3.06 mmoles) and diisopropylethylamine (1.06 mL, 6.12 mmoles)were stirred together in dry dichloromethane (50 mL) and treated withethyl isocyanatoacetate (360 uL, 3.21 mmoles). The mixture was stirredfor under argon overnight, washed twice with 1 molar hydrochloric acid,dried and evaporated. The residue was dissolved in ethanol (15 mL) andtreated with 1 molar sodium hydroxide solution (2.0 mL) and 6 molarsodium hydroxide solution (2.0 mL) and stirred for 4 hours. The mixturewas partitioned between ethyl acetate and 1 molar hydrochloric acid, theorganic solution washed with 1 molar hydrochloric acid, dried andevaporated to a solid. The solid was triturated with diethyl ether,collected, washed with a small amount of diethyl ether and hexane toafford the title compound (570 mg, 47%). 1H NMR (400 MHz, DMSO-d₆) δ ppm13.10 (br. s, 1H), 10.19 (t, J=5.56 Hz, 1H), 4.83-4.94 (m, 1H), 4.63 (t,J=11.49 Hz, 1H), 4.13 (d, J=5.81 Hz, 2H), 3.93 (dd, J=11.12, 4.04 Hz,2H), 3.30-3.37 (m, 2H), 2.56 (m, 2H), 2.21-2.33 (m, 2H), 1.79 (d,J=12.88 Hz, 2H), 1.61 (s, 3H), 1.52 (d, J=10.61 Hz, 2H), 1.28 (q,J=12.97 Hz, 2H), 1.11-1.18 (m, 1H).

Example 34

N-{[3-{[4-(1,1-Dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1-(2-thienyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

34a)1-{[4-(1,1-Dimethylethyl)phenyl]methyl}-3-(2-thienyl)-2,4,6(1H,3H,5H)-pyrimidinetrione.A mixture of 2-thienyl isocyanate (970 mg, 7.76 mmoles) and4-t-butylbenzylamine (1.38 mL, 7.76 mmoles) in dichloromethane (100 mL)was stirred under inert atmosphere for 2 hours. Malonyl dichloride (754uL, 7.76 mmoles) was added (became dark on addition) and the mixture washeated under reflux for 1.5 hours. The mixture was washed with 1 molarhydrochloric acid and evaporated. Flash chromatography (10-35% ethylacetate-hexane) afforded the title (274 mg, 10%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 7.57 (dd, J=5.56, 1.52 Hz, 1H), 7.27-7.36 (m, 4H), 7.04(dd, J=5.43, 3.66 Hz, 1H), 6.96 (dd, J=3.66, 1.39 Hz, 1H), 4.90 (s, 2H),3.94 (s, 2H), 1.26 (s, 9H).

34b)N-{[3-{[4-(1,1-Dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1-(2-thienyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.1-{[4-(1,1-Dimethylethyl)phenyl]methyl}-3-(2-thienyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(270 mg, 0.66 mmoles) and diisopropylethylamine (228 uL, 1.32 mmoles)were stirred together in dry chloroform (5 mL) and treated with ethylisocyanatoacetate (56.4 uL, 0.66 mmoles). The mixture was stirred underargon overnight, washed twice with 1 molar hydrochloric acid, dried andevaporated. The residue was dissolved in ethanol (5 mL) and treated with6 molar sodium hydroxide solution (1.5 mL) and stirred overnight. Themixture was partitioned between ethyl acetate and 1 molar hydrochloricacid, the organic solution washed with 1 molar hydrochloric acid andevaporated, taken up in diethyl ether and warmed with decolorizingcharcoal. The mixture was filtered and evaporated to a foam. The solidwas triturated with hexane and collected. Preparative HPLC (10-100%acetonitrile-water-0.1% TFA) gave the title compound (120 mg, 40%). 1HNMR (400 MHz, DMSO-d₆) δ ppm 13.15 (br. s, 1H), 10.09 (br. s, 1H), 7.60(dd, J=5.05, 1.77 Hz, 1H), 7.32-7.38 (m, 2H), 7.26-7.31 (m, 2H),7.04-7.10 (m, 2H), 4.98 (s, 2H), 4.12-4.19 (m, 2H), 1.26 (s, 9H).

Example 35

N-({1-Cyclohexyl-6-hydroxy-3-[3-(4-morpholinyl)propyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

35a)1-Cyclohexyl-3-[3-(4-morpholinyl)propyl]-2,4,6(1H,3H,5H)-pyrimidinetrione.A mixture of cyclohexyl isocyanate (638 mg, 5.0 mmoles) and3-morpholinopropylamine (730 mL, 5.0 mmoles) in dichloromethane (50 mL)was stirred under inert atmosphere for 3 hours. Malonyl dichloride (486uL, 5.0 mmoles) was added and the mixture was heated under reflux for 3hours. The mixture was washed with water, sodium bicarbonate solutionand evaporated. Flash chromatography (0-5% methanol-dichloromethane)afforded the title (785 mg, 47%).

35b)N-({1-Cyclohexyl-6-hydroxy-3-[3-(4-morpholinyl)propyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine.1-Cyclohexyl-3-[3-(4-morpholinyl)propyl]-2,4,6(1H,3H,5H)-pyrimidinetrione(785 mg, 2.32 mmoles) and diisopropylethylamine (805 uL, 4.65 mmoles)were stirred together in dry dichloromethane (50 mL) and treated withethyl isocyanatoacetate (260 uL, 2.32 mmoles). The mixture was stirredunder argon overnight, washed with water and brine, dried andevaporated. The residue was dissolved in ethanol (10 mL) and treatedwith 1 molar sodium hydroxide solution (2.0 mL) and 6 molar sodiumhydroxide solution (1.0 mL) and stirred for 2 hours. The mixture wasdiluted with 1 molar hydrochloric acid and extracted with ethyl acetate(×3), the organic solution washed with brine and evaporated. The residuewas purified by preparative HPLC (10-70% acetonitrile-water-0.1% TFA) togive the title compound (90 mg, 9%). 1H NMR (400 MHz, DMSO-d₆) δ ppm13.16 (br. s., 1H), 10.15 (br. s., 1H), 4.64 (t, J=11.62 Hz, 1H), 4.15(d, J=3.28 Hz, 2H), 3.88 (t, J=6.44 Hz, 6H), 2.86-3.31 (br. m, 6H),2.18-2.39 (m, 2H), 1.90-2.05 (m, 2H), 1.88-2.05 (m, 2H), 1.80 (d,J=12.88 Hz, 2H), 1.63 (s, 3H), 1.21-1.38 (m, 2H), 1.03-1.20 (m, 1H)

Example 36

N-{[3-{[4-(1,1-Dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1-(3-pyridinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

36a)1-{[4-(1,1-Dimethylethyl)phenyl]methyl}-3-(3-pyridinyl)-2,4,6(1H,3H,5H)-pyrimidinetrione.A mixture of pyridine 3-isocyanate (622 mg, 5.18 mmoles) and4-t-butylbenzylamine (912 uL, 5.18 mmoles) in dichloromethane (50 mL)was stirred overnight. The urea was purified by flash chromatography(ethyl acetate), taken up in methoxyethanol (10 mL), treated withdiethyl malonate (1.0 mL, 6.58 mmoles) and sodium ethoxide (1.0 mL of a21 molar solution in ethanol) and heated under reflux for 24 hours in aninert atmosphere. The mixture was cooled, diluted with ethyl acetate andwashed with brine. The organic solution was evaporated and purified byflash chromatography (10-100% ethyl acetate in hexane) to give the titlecompound (340 mg, 19%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (dd,J=4.80, 1.52 Hz, 1H), 8.48 (d, J=2.02 Hz, 1H), 7.75 (d, J=8.08 Hz, 1H),7.57 (dd, J=8.21, 4.93 Hz, 1H), 7.29-7.36 (m, 4H), 3.55 (s, 2H), 1.26(s, 9H).

36b)N-{[3-{[4-(1,1-Dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1-(3-pyridinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.1-{[4-(1,1-Dimethylethyl)phenyl]methyl}-3-(3-pyridinyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(340 mg, 0.96 mmoles) and diisopropylethylamine (334 uL, 1.93 mmoles)were stirred together in dry chloroform (25 mL) and treated with ethylisocyanatoacetate (108 uL, 0.96 mmoles). The mixture was stirred underargon overnight, washed with 1 molar hydrochloric acid and brine, driedand evaporated. The residue was dissolved in ethanol (5 mL) and treatedwith 1 molar sodium hydroxide solution (2.0 mL) and 6 molar sodiumhydroxide solution (2.0 mL) and stirred overnight. The mixture wasdiluted with 1 molar hydrochloric acid and extracted with ethyl acetate(×2), the organic solution washed with brine and evaporated. The solidresidue was slurried in hot ethanol, collected and recrystallized fromethanol-water to give the title compound (100 mg, 23%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.11 (s, 1H), 10.09 (s, 1H), 8.62 (dd, J=4.67, 1.39 Hz,1H), 8.58 (s, 1H), 7.86 (d, J=7.83 Hz, 1H), 7.55 (dd, J=8.08, 4.80 Hz,1H), 7.28-7.37 (m, 4H), 5.00 (s, 2H), 4.11-4.19 (m, 2H), 1.26 (s, 9H).

Example 37

N-({1-Cyclohexyl-3-[(2-fluorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

37a) EthylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate.Ethyl isocyanatoacetate (9.7 mL, 86.32 mmoles) in dichloromethane (80mL) was added dropwise to a stirred solution of1-cyclohexylpyrimidinetrione (16.5 g, 78.5 mmoles) anddiisopropylethylamine (27.2 mL, 157 mmoles) in dichloromethane (120 mL).The mixture was stirred for 3 hours, 1 molar hydrochloric acid wasadded, causing the title compound to precipitate. The solid wascollected and washed with 1 molar hydrochloric acid. The solid wasslurried in diethyl ether, collected, washed with diethyl ether andhexane then dried to give the title compound (23 g, 86%). 1H NMR (400MHz, DMSO-d₆) δ ppm 11.92 (br. s., 1H), 9.91 (br. s., 1H), 4.57 (s, 1H),4.15 (q, J=6.99 Hz, 4H), 2.26 (d, J=11.62 Hz, 2H), 1.78 (d, J=12.63 Hz,2H), 1.50-1.68 (m, 3H), 1.17-1.36 (m, 5H), 1.11 (q, J=13.05 Hz, 1H)

37b)N-({1-Cyclohexyl-3-[(2-fluorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine.A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles)and 2-fluorobenzyl bromide (380 mg, 2.0 mmoles) in dimethylformamide (5mL) was vigorously stirred at 100° C. for 3 hours. The mixture waspoured into 1 molar hydrochloric acid and extracted with ethyl acetate.The organic solution was washed with 1 molar hydrochloric acid andevaporated. The residue was purified by flash chromatography (10-50%ethyl acetate in hexane), the required fractions evaporated, dissolvedin ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6molar sodium hydroxide solution (1.0 mL) added. The mixture was stirredovernight, acidified and extracted with ethyl acetate (×2), the combinedextracts washed with 1 molar hydrochloric acid, dried and evaporated togive the title compound (163 mg, 39%). 1H NMR (400 MHz, DMSO-d₆) δ ppm13.09 (br. s, 1H), 10.13 (br. s, 1H), 7.28-7.34 (m, 1H), 7.12-7.22 (m,3H), 5.05 (s, 2H), 4.64 (t, J=12.13 Hz, 1H), 4.10-4.16 (m, 2H), 2.26(qd, J=12.38, 2.78 Hz, 2H), 1.78 (d, J=12.88 Hz, 2H), 1.63 (s, 3H), 1.28(q, J=12.88 Hz, 2H), 1.06-1.17 (m, 1H).

Example 38

N-({3-[(2-Chlorophenyl)methyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles)and 2-chlorobenzyl bromide (300 mg, 1.5 mmoles) in dimethylformamide (5mL) was vigorously stirred at 100° C. for 3 hours. The mixture waspoured into 1 molar hydrochloric acid and extracted with ethyl acetate.The organic solution was washed with 1 molar hydrochloric acid andevaporated. The residue was purified by flash chromatography (10-50%ethyl acetate in hexane), the required fractions evaporated, dissolvedin ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6molar sodium hydroxide solution (1.0 mL) added. The mixture was stirredovernight, acidified and extracted with ethyl acetate (×2), the combinedextracts washed with 1 molar hydrochloric acid, dried and evaporated togive the title compound (193 mg, 44%). 1H NMR (400 MHz, DMSO-d₆) δ ppm13.11 (br. s, 1H), 10.13 (br. s, 1H), 7.45-7.50 (m, 1H), 7.26-7.32 (m,2H), 7.05-7.09 (m, 1H), 5.05 (s, 2H), 4.65 (t, J=11.87 Hz, 1H), 4.13 (d,J=5.56 Hz, 2H), 2.20-2.30 (m, 2H), 1.79 (d, J=13.14 Hz, 2H), 1.59-1.69(m, 3H), 1.28 (q, J=12.97 Hz, 2H), 1.06-1.16 (m, 1H).

Example 39

N-({1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles)and 6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene(250 mg, 0.89 mmoles) in dimethylformamide (5 mL) was vigorously stirredat 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloricacid and extracted with ethyl acetate. The organic solution was washedwith 1 molar hydrochloric acid and evaporated. The residue was purifiedby flash chromatography (10-50% ethyl acetate in hexane), the requiredfractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodiumhydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0mL) added. The mixture was stirred overnight, acidified and extractedwith ethyl acetate (×2), the combined extracts washed with 1 molarhydrochloric acid, dried and evaporated to give the title compound (156mg, 35%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.07 (br. s., 1H), 7.24 (dd,J=4.80, 3.28 Hz, 2H), 6.98 (dd, J=8.21, 1.39 Hz, 1H), 4.93 (s, 2H), 4.66(t, J=11.87 Hz, 1H), 4.13 (d, J=5.56 Hz, 2H), 2.19-2.36 (m, 2H), 1.79(d, J=12.63 Hz, 2H), 1.62 (s, 7H), 1.01-1.37 (m, 15H).

Example 40

N-({1-Cyclohexyl-3-[(2,4-dimethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles)and 2,4-dimethylbenzyl bromide (400 mg, 2.0 mmoles) in dimethylformamide(5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture waspoured into 1 molar hydrochloric acid and extracted with ethyl acetate.The organic solution was washed with 1 molar hydrochloric acid andevaporated. The residue was purified by flash chromatography (10-50%ethyl acetate in hexane), the required fractions evaporated, dissolvedin ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6molar sodium hydroxide solution (1.0 mL) added. The mixture was stirredovernight, acidified and extracted with ethyl acetate (×2), the combinedextracts washed with 1 molar hydrochloric acid, dried and evaporated togive the title compound (173 mg, 40%). 1H NMR (400 MHz, DMSO-d₆) δ ppm13.10 (br. s., 1H), 10.15 (br. s., 1H), 2.31 (s, 3H), 2.18-2.29 (m, 5H),1.78 (d, J=13.14 Hz, 2H), 1.62 (d, J=10.36 Hz, 3H), 1.28 (q, J=12.72 Hz,2H), 1.12 (t, J=12.88 Hz, 1H).

Example 41

N-({1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-[(2,4,6-trifluorophenyl)methyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles)and 2,4,6-trifluorobenzyl bromide (337 mg, 1.5 mmoles) indimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours.The mixture was poured into 1 molar hydrochloric acid and extracted withethyl acetate. The organic solution was washed with 1 molar hydrochloricacid and evaporated. The residue was purified by flash chromatography(10-50% ethyl acetate in hexane), the required fractions evaporated,dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixturewas stirred overnight, acidified and extracted with ethyl acetate (×2),the combined extracts washed with 1 molar hydrochloric acid, dried andevaporated to give the title compound (240 mg, 53%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.06 (br. s, 1H), 10.08 (br. s, 1H), 7.11-7.19 (m, 2H),5.06 (s, 2H), 4.61 (t, J=12.00 Hz, 1H), 4.12 (d, J=5.81 Hz, 2H),2.19-2.30 (m, J=12.25, 12.25, 12.13, 2.53 Hz, 2H), 1.78 (d, J=12.88 Hz,2H), 1.59 (t, J=13.01 Hz, 3H), 1.28 (q, J=12.88 Hz, 2H), 1.06-1.17 (m,1H).

Example 42

N-[(1-Cyclohexyl-6-hydroxy-3-{[4-(1-methylethyl)phenyl]methyl}-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. Potassium carbonate (1.0 g, 7.24 mmoles) and4-isopropylbenzyl chloride (250 mg, 1.5 mmoles) in dimethylacetamide (5mL) was vigorously stirred at 100° C. for 3 hours. The mixture waspoured into 1 molar hydrochloric acid and extracted with ethyl acetate.The organic solution was washed with 1 molar hydrochloric acid andevaporated. The residue was purified by flash chromatography (10-50%ethyl acetate in hexane), the required fractions evaporated, dissolvedin ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6molar sodium hydroxide solution (1.0 mL) added. The mixture was stirredovernight, acidified and extracted with ethyl acetate (×2), the combinedextracts washed with 1 molar hydrochloric acid, dried and evaporated togive the title compound (161 mg, 36%). 1H NMR (400 MHz, DMSO-d₆) δ ppm13.10 (s, 1H), 10.14 (s, 1H), 7.16-7.24 (m, 4H), 4.95 (s, 2H), 4.64 (t,J=11.37 Hz, 1H), 4.13 (d, J=5.56 Hz, 2H), 2.79-2.90 (m, J=6.86, 6.86,6.86, 6.86, 6.86, 6.86 Hz, 1H), 2.20-2.32 (m, 2H), 1.78 (d, J=12.88 Hz,2H), 1.62 (d, J=11.12 Hz, 3H), 1.22-1.34 (m, 2H), 1.09-1.20 (m, 7H).

Example 43

N-({1-Cyclohexyl-3-[(2-ethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(680 mg, 2.0 mmoles), pulv. potassium carbonate (2.0 g, 14.46 mmoles)and a mixture of both 2- and 4-ethylbenzyl chloride (464 mg, 3.0 mmoles)in dimethylacetamide (8.0 mL) was vigorously stirred at 100° C. for 3hours. The mixture was poured into 1 molar hydrochloric acid andextracted with ethyl acetate. The organic solution was washed with 1molar hydrochloric acid and evaporated. The residue was separated bypreparative HPLC (80% acetonitrile-water-0.1% TFA), to give a) ethylN-({1-cyclohexyl-3-[(2-ethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycinate(100 mg, 11%) and b) ethylN-({1-cyclohexyl-3-[(4-ethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycinate(300 mg, 33%). Product a) was dissolved in ethanol (5 mL) and 1 molarsodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution(1.0 mL) added. The mixture was stirred overnight, acidified andextracted with ethyl acetate (×2), the combined extracts washed with 1molar hydrochloric acid, dried and evaporated to give the title compound(58 mg, 62%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.00 (br. s., 1H), 10.15(br. s., 1H), 7.14-7.23 (m, 2H), 7.07-7.15 (m, 1H), 6.88 (d, J=7.58 Hz,1H), 5.03 (s, 2H), 4.65 (t, J=11.75 Hz, 1H), 4.13 (d, J=5.56 Hz, 2H),2.72 (q, J=7.49 Hz, 2H), 2.17-2.35 (m, 2H), 1.78 (d, J=12.63 Hz, 2H),1.56-1.69 (m, 3H), 1.23-1.35 (m, 2H), 1.20 (t, J=7.58 Hz, 3H), 1.04-1.17(m, 1H).

Example 44

N-({1-Cyclohexyl-3-[(4-ethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

EthylN-({1-cyclohexyl-3-[(4-ethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycinate(product b from example 43) was dissolved in ethanol (5 mL) and 1 molarsodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution(1.0 mL) added. The mixture was stirred overnight, acidified andextracted with ethyl acetate (×2), the combined extracts washed with 1molar hydrochloric acid, dried and evaporated to give the title compound(195 mg, 69%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.13 (br. s., 1H), 10.15(s, 1H), 7.18-7.24 (m, 2H), 7.13-7.18 (m, 2H), 4.95 (s, 2H), 4.64 (t,J=11.62 Hz, 1H), 4.13 (d, J=5.81 Hz, 2H), 2.56 (q, J=7.58 Hz, 2H),2.20-2.31 (m, 2H), 1.78 (d, J=12.13 Hz, 2H), 1.61 (d, J=10.36 Hz, 3H),1.28 (q, J=12.72 Hz, 2H), 1.06-1.17 (m, 4H).

Example 45

N-({1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-[(2,4,6-trimethylphenyl)methyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (1.0 g, 7.24 mmoles) and2,4,6-trimethylbenzyl chloride (339 mg, 1.5 mmoles) in dimethylacetamide(5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture waspoured into 1 molar hydrochloric acid and extracted with ethyl acetate.The organic solution was washed with 1 molar hydrochloric acid andevaporated. The residue was purified by flash chromatography (10-50%ethyl acetate in hexane), the required fractions evaporated, dissolvedin ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6molar sodium hydroxide solution (1.0 mL) added. The mixture was stirredovernight, acidified and extracted with ethyl acetate (×2), the combinedextracts washed with 1 molar hydrochloric acid, dried and evaporated togive the title compound (61 mg, 13%). 1H NMR (400 MHz, DMSO-d₆) δ ppm13.07 (s, 1H), 10.07 (s, 1H), 6.77 (s, 2H), 4.99 (s, 2H), 4.59 (t,J=12.00 Hz, 1H), 4.08-4.14 (m, 2H), 2.21-2.29 (m, 8H), 2.14-2.20 (m,4H), 1.77 (d, J=12.63 Hz, 2H), 1.52-1.64 (m, 3H), 1.27 (q, J=12.88 Hz,2H), 1.05-1.17 (m, 1H).

Example 46

N-{[1-Cyclohexyl-3-(2-cyclohexylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (1.0 g, 7.24 mmoles) and2-cyclohexylethyl bromide (287 mg, 1.5 mmoles) in dimethylacetamide (8mL) was vigorously stirred at 100° C. for 3 hours. The mixture waspoured into 1 molar hydrochloric acid and extracted with ethyl acetate.The organic solution was washed with 1 molar hydrochloric acid andevaporated. The residue was purified by flash chromatography (10-50%ethyl acetate in hexane), the required fractions evaporated, dissolvedin ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6molar sodium hydroxide solution (1.0 mL) added. The mixture was stirredovernight, acidified and extracted with ethyl acetate (×2), the combinedextracts washed with 1 molar hydrochloric acid, dried and evaporated.Recrystallization from toluene gave the title compound (180 mg, 42%). 1HNMR (400 MHz, DMSO-d₆) δ ppm 10.15 (br. s., J=5.43, 5.43 Hz, 1H), 4.63(t, J=11.62 Hz, 1H), 4.07-4.19 (m, 2H), 3.72-3.88 (m, 2H), 2.18-2.36 (m,2H), 1.50-1.87 (m, 10H), 1.35-1.47 (m, 2H), 1.04-1.35 (m, 7H), 0.91 (q,J=11.62 Hz, 2H).

Example 47

N-[(3-{[3,5-Bis(methyloxy)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (1.5 g, 11 mmoles) and3,5-dimethoxybenzyl bromide (300 mg, 1.3 mmoles) in dimethylacetamide (5mL) was vigorously stirred at 100° C. for 3 hours. The mixture waspoured into 1 molar hydrochloric acid and extracted with ethyl acetate.The organic solution was washed with 1 molar hydrochloric acid andevaporated. The residue was purified by flash chromatography (10-50%ethyl acetate in hexane), the required fractions evaporated, dissolvedin ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6molar sodium hydroxide solution (1.0 mL) added. The mixture was stirredovernight, acidified and extracted with ethyl acetate (×2), the combinedextracts washed with 1 molar hydrochloric acid, dried and evaporated.Recrystallization from toluene gave the title compound (190 mg, 41%). 1HNMR (400 MHz, DMSO-d₆) δ ppm 13.11 (s, 1H), 10.15 (s, 1H), 6.40 (s, 3H),4.92 (s, 2H), 4.64 (t, J=11.87 Hz, 1H), 4.09-4.17 (m, 2H), 3.70 (s, 6H),2.26 (s, 2H), 1.78 (d, J=12.63 Hz, 2H), 1.62 (d, J=11.62 Hz, 3H), 1.28(q, J=13.05 Hz, 2H), 1.06-1.17 (m, 1H).

Example 48

N-{[1-Cyclohexyl-6-hydroxy-3-(2-naphthalenylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

A mixture of ethylN-[(3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(100 mg, 0.29 mmoles), 2-bromomethylnaphthalene (195 mg, 0.88 mmoles)and polymer-bound2-tert-butylimino-2-diethylamine-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine(pol-BEMP, 0.88 mmoles) in DMF (3 mL) was heated in a microwavesynthesiser at 120° C. for 20 minutes. After cooling, the mixture wasfiltered, and the solids washed with dichloromethane (3×3 mL). Thecombined filtrate was evaporated and purified by flash chromatography(ethyl acetate-hexane) to obtain the desired intermediate ester. Thecrude ester was dissolved in ethanol (4 mL) and 1M aqueous NaOH (1 mL)and the solution stirred for 2 hours, then neutralized by addition of 1Maqueous HCl. The solid was collected, washed with water (3×4 mL) anddried under vacuum overnight to give the title compound (77 mg, 29%). 1HNMR (400 MHz, CDCl₃) δ ppm 1.13-1.42 (m, 4H) 1.56-1.72 (m, 3H) 1.77-1.90(m, 2H) 2.26-2.44 (m, 2H) 4.24 (dd, J=2.2, 5.7 Hz, 2H) 4.64-4.84 (m, 1H)5.24 (s, 2H) 7.40-7.50 (m, 2H) 7.55 (dt, J=2.1, 8.3 Hz, 1H) 7.75-7.90(m, 4H) 10.21-10.34 (m, 1H)

Example 49

N-({1-Cyclohexyl-6-hydroxy-3-[(4-methylphenyl)methyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

Using 4-methylbenzyl bromide in place of 2-bromomethylnaphthylene, thetitle compound was prepared in 27% yield (67 mg) following theprocedures described in example 48. 1H NMR (400 MHz, CDCl₃) δ ppm1.10-1.43 (m, 4H) 1.52-1.72 (m, 3H) 1.76-1.93 (m, 2H) 2.20-2.43 (m, 5H)4.22 (dd, J=3.4, 5.7 Hz, 2H) 4.64-4.82 (m, 1H) 5.04 (s, 2H) 7.06-7.16(m, 2H) 7.29-7.36 (m, 2H) 10.15-10.36 (m, 1H)

Example 50

N-{[3-(4-Biphenylylmethyl)-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Using 4-bromomethylbiphenyl in place of 2-bromomethylnaphthylene, thetitle compound was prepared in 17% yield (48 mg) following theprocedures described in example 48. 1H NMR (400 MHz, CDCl₃) δ ppm1.13-1.45 (m, 3H) 1.55-1.75 (m, 3H) 1.76-1.91 (m, 2H) 2.24-2.46 (m, 2H)4.23 (dd, J=3.4, 5.7 Hz, 2H) 4.62-4.92 (m, 1H) 5.12 (s, 2H) 5.42-5.97(m, 2H) 7.29-7.38 (m, 1H) 7.38-7.46 (m, 2H) 7.46-7.61 (m, 6H)10.14-10.42 (m, 1H)

Example 51

N-[(3-{[4-(1,3-Benzoxazol-2-yl)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Using 2-[4-(bromomethyl)phenyl]-1,3-benzoxazole in place of2-bromomethylnaphthylene, the title compound was prepared in 10% yield(30 mg) following the procedures described in example 48. 1H NMR (400MHz, CDCl₃) δ ppm 1.11-1.42 (m, 3H) 1.57-1.72 (m, 3H) 1.74-1.91 (m, 2H)2.27-2.43 (m, 2H) 4.16 (dd, J=3.4, 5.7 Hz, 2H) 4.67-4.95 (m, 3H)5.09-5.23 (m, 2H) 7.32-7.42 (m, 3H) 7.53-7.62 (m, 3H) 7.74-7.79 (m, 1H)8.18-8.27 (m, 1H) 10.22-10.42 (m, 1H)

Example 52

N-({3-[2-(4-Biphenylyl)-2-oxoethyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

Using 2-bromo-4′-phenylacetophenone in place of2-bromomethylnaphthylene, the title compound was prepared in 8% yield(24 mg) following the procedures described in example 48. 1H NMR (400MHz, CDCl₃) δ ppm 1.11-1.27 (m, 1H) 1.27-1.43 (m, 2H) 1.59-1.78 (m, 3H)1.78-1.20 (m, 2H) 2.25-2.43 (m, 2H) 4.15-4.31 (m, 2H) 4.62-4.87 (m, 1H)5.36-5.42 (m, 2H) 7.39-7.45 (m, 1H) 7.45-7.53 (m, 2H) 7.61-7.67 (m, 2H)7.69-7.76 (m, 2H) 8.08 (d, J=8.3 Hz, 2H) 10.07-10.42 (m, 1H)

Example 53

N-[(1,3-Bis{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

53a) N,N′-Bis{[4-(1,1-dimethylethyl)phenyl]methyl}urea. Diphosgene (725uL, 6.0 mmoles) was added to a solution of 4-t-butylbenzylamine (880 uL,5.0 mmoles) in ethyl acetate (20 mL) under nitrogen atmosphere at roomtemperature. A solid precipitated and the mixture was then heated to 70°C. until the solid dissolved. After stirring for 1 hour,4-t-butylbenzylamine (880 uL, 5.0 mmoles) was added and the mixture wasstirred for 2 hours. Diisopropylethylamine (1.0 mL, 5.75 uL) was addedand the mixture was stirred for 1 hour, washed with 1 molar hydrochloricacid, dried and evaporated to an oil which solidified on standingovernight to give the title compound (710 mg, 40%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 7.30-7.38 (m, 4H), 7.17 (d, J=8.34 Hz, 4H), 6.34 (t,J=5.94 Hz, 2H), 4.18 (d, J=5.81 Hz, 4H), 1.27 (s, 18H).

53b)1,3-Bis{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione.Malonyl dichloride (195 uL, 2.0 mmoles) was added to a stirred solutionof N,N′-bis{[4-(1,1-dimethylethyl)phenyl]methyl}urea in dichloromethane(80 mL) and the mixture was heated under reflux for 2 hours. The mixturewas washed with 1 molar hydrochloric acid, and purified by flashchromatography (0-30% ethyl acetate in hexane) to give the titlecompound (700 mg, 84%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.29-7.35 (m,4H), 7.21-7.29 (m, 4H), 4.87 (s, 4H), 3.86-3.93 (s, 2H), 1.25 (s, 18H).

53c)N-[(1,3-Bis{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.A mixture of1,3-bis{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione(700 mg, 1.66 mmoles) and diisopropylethylamine (574 uL, 3.32 mmoles)was stirred in dichloromethane (50 mL) and treated with ethylisocyanatoacetate (202 uL, 1.8 mmoles). The mixture was stirred for 5hours, then warmed to complete reaction. The mixture was washed with 1molar hydrochloric acid, evaporated, taken up in ethanol-6 molar sodiumhydroxide solution, stirred and gently warmed to complete hydrolysis.The mixture was acidified and extracted into ethyl acetate. The extractswere evaporated and a solid obtained from aqueous ethanol to give thetitle compound (700 mg, 81%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.67 (s,1H), 7.24-7.30 (m, 4H), 7.16 (d, J=8.59 Hz, 4H), 4.94 (s, 4H), 3.42 (d,J=4.04 Hz, 2H), 1.25 (s, 18H).

Example 54

N-{[1-Cyclohexyl-6-hydroxy-3-(4-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

A solution of cyclohexylisocyanate (1252 mg, 10 mmoles) indichloromethane (20 mL) was added dropwise to a solution of4-methylcyclohexylamine (1132 mg, 10 mmoles) in dichloromethane (100mL). The solution was allowed to stir at room temperature for 2 hours,then the solvent evaporated and the residue dissolved in dichloromethane(10 mL) along with malonyl chloride (10 mmol). The mixture was heated ina microwave synthesiser (80° C./20 min). All volatiles were evaporatedand the residue dissolved in of chloroform (10 mL) along with ethylisocyanatoacetate (10 mmol), then the mixture was stirred at roomtemperature for 2 hours. Solvent was evaporated and the residue waspurified by flash chromatography (ethyl acetate-hexane) to obtain theintermediate ester. The ester was dissolved in a mixture of ethanol (4mL) and 1M aqueous NaOH (1 mL). The solution was stirred for 2 hours andneutralized by addition of 1M aqueous HCl. The solid was collected,washed with water (3×4 mL) and dried under vacuum overnight to give thetitle compound (443 mg, 11%). 1H NMR (400 MHz, CDCl₃) δ ppm 0.85-0.96(m, 2H) 1.10-1.13 (m, 3H) 1.16-1.50 (m, 6H), 1.53-1.72 (m, 6H) 1.73-1.89(m, 3H) 2.25-2.47 (m, 3H) 2.50-2.66 (m, 1H) 4.01-4.08 (m, 1H) 4.23 (d,J=5.8 Hz, 1H) 4.60-4.82 (m, 2H) 10.25-10.36 (m, 1H)

Example 55

N-({1-Cyclohexyl-3-[4-(1,1-dimethylethyl)cyclohexyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

Using 4-tert-butylcyclohexylamine in place of 4-methylcyclohexylamine,the title compound was prepared in 21% yield (931 mg) following theprocedures described in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm0.77-0.94 (m, 13H) 1.03-1.45 (m, 6H) 1.45-1.77 (m, 5H) 1.77-1.97 (m, 3H)2.18-2.48 (m, 3H) 4.01-4.10 (m, 1H) 4.24 (d, J=5.6 Hz, 1H) 4.58-4.82 (m,2H) 10.26-10.36 (m, 1H)

Example 56

N-[(1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Using aniline in place of 4-methylcyclohexylamine, the title compoundwas prepared in 5% yield (198 mg) following the procedures described inexample 54. 1H NMR (400 MHz, CDCl₃) δ ppm 1.02-1.46 (m, 5H) 1.54-1.78(m, 3H) 1.78-1.98 (m, 2H) 2.26-2.47 (m, 2H) 4.21 (dd, J=5.8, 19 Hz, 2H)4.69-4.87 (m, 1H) 7.16-7.31 (m, 2H) 7.40-7.46 (m, 3H) 10.06-10.42 (m,1H)

Example 57

N-({1-Cyclohexyl-3-[4-(1,1-dimethylethyl)phenyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

Using 4-tert-butylaniline in place of 4-methylcyclohexylamine, the titlecompound was prepared in 7% yield (321 mg) following the proceduresdescribed in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm 1.09-1.24 (m, 1H)1.26-1.43 (m, 13H) 1.58-1.77 (m, 3H) 1.78-1.91 (m, 2H) 2.27-2.49 (m, 2H)4.22 (dd, J=14.7, 20.2 Hz, 2H) 4.68-4.88 (m, 1H) 7.16 (dd, J=8.6, 14.4Hz, 2H) 7.51 (dd, J=14.4 Hz, 2H) 10.10-10.42 (m, 1H)

Example 58

N-{[1-Cyclohexyl-3-(cyclohexylmethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Using cyclohexylmethylamine in place of 4-methylcyclohexylamine, thetitle compound was prepared in 22% yield (442 mg) following theprocedures described in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm0.85-1.11 (m, 2H) 1.11-1.28 (m, 5H) 1.28-1.48 (m, 2H) 1.55-1.79 (m, 10H)1.79-1.91 (m, 2H) 2.35 (dq, J=3.0, 12.4 Hz, 2H) 3.76 (d, J=1.4, 7.2 Hz,2H) 4.24 (dd, J=3.0, 7.2 Hz, 2H) 4.65-4.83 (m, 1H) 10.17-10.33 (m, 1H)

Example 59

N-[(3-Cycloheptyl-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Using cycloheptylamine in place of 4-methylcyclohexylamine, the titlecompound was prepared in 29% yield (583 mg) following the proceduresdescribed in example 54. 1H NMR (400 MHz, DMSO-d₆) ppm 1.03-1.19 (m, 2H)1.19-1.34 (m, 3H) 1.34-1.84 (m, 14H) 2.14-2.36 (m, 4H) 3.17 (s, 1H) 4.06(d, J=5.6 Hz, 2H) 4.56-4.71 (m, 1H) 4.73-4.89 (m, 1H) 10.11-10.23 (m,1H)

Example 60

N-[(3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-tricyclo[3,3,1,1^(3,7)]dec-1-yl-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Using 1-adamantanamine hydrochloride in place of4-methylcyclohexylamine, the title compound was prepared in 3% yield (66mg) following the procedures described in example 54. 1H NMR (400 MHz,CDCl₃) δ ppm 1.12-1.43 (m, 4H) 1.54-1.88 (m, 12H) 2.03-2.20 (m, 3H)2.23-2.28 (m, 2H) 2.45-2.57 (m, 6H) 4.21 (d, J=5.8 Hz, 2H) 4.50-4.70 (m,1H) 10.16-10.31 (m, 1H)

Example 61

N-({1-[(1R,2R,4S)-Bicyclo[2,2,1]hept-2-yl]-3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

Using exo-2-aminonorbornane in place of 4-methylcyclohexylamine, thetitle compound was prepared in 30% yield (604 mg) following theprocedures described in example 54. 1H NMR (400 MHz, DMSO-d₆) δ ppm0.96-1.34 (m, 9H) 1.35-1.67 (m, 6H) 1.67-1.84 (m, 3H) 2.20-2.36 (m, 4H)4.01 (d, J=5.6 Hz, 2H) 4.55-4.72 (m, 2H) 10.11-10.20 (m, 1H)

Example 62

N-{[1-Cyclohexyl-6-hydroxy-3-(3-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Using 3-methylcyclohexylamine in place of 4-methylcyclohexylamine, thetitle compound was prepared in 41% yield (836 mg) following theprocedures described in example 54. 1H NMR (400 MHz, DMSO-d₆) δ ppm 0.89(d, J=6.6 Hz, 3H) 0.97-1.48 (m, 8H) 1.49-1.67 (m, 6H) 1.69-1.86 (m, 3H)2.08-2.37 (m, 4H) 4.06 (d, J=5.6 Hz, 2H) 4.55-4.76 (m, 2H) 10.12-10.26(m, 1H)

Example 63

N-[(3-Cyclohexyl-1-cyclopropyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Using cyclopropylamine in place of 4-methylcyclohexylamine, the titlecompound was prepared in 20% yield (351 mg) following the proceduresdescribed in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm 0.95-1.08 (m,1H), 1.12-1.28 (m, 4H), 1.29-1.42 (m, 1H), 1.57-1.80 (m, 6H), 1.80-1.89(m, 1H), 2.28-2.42 (m, 2H), 3.76 (d, J=7.1 Hz, 2H), 4.24 (dd, J=5.6, 3.5Hz, 2H), 4.66-4.82 (m, 1H), 10.21-10.31 (m, 1H).

Example 64

N-[(1-Cyclobutyl-3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Using cyclobutylamine in place of 4-methylcyclohexylamine, the titlecompound was prepared in 23% yield (424 mg) following the proceduresdescribed in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm 1.14-1.46 (m, 4H)1.56-1.98 (m, 7H) 2.14-2.46 (m, 4H) 2.80-3.00 (m, 2H) 4.24 (d, J=5.6 Hz,2H) 4.58-4.83 (m, 1H) 5.08-5.33 (m, 2H) 10.22-10.32 (m, 1H)

Example 65

N-[(3-Cyclohexyl-1-cyclopentyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Method 1

65.1 Using cyclopentylamine in place of 4-methylcyclohexylamine, thetitle compound was prepared in 19% yield (357 mg) generally followingthe procedures described in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm1.14-1.45 (m, 4H) 1.52-1.73 (m, 5H) 1.75-2.00 (m, 7H) 2.00-2.16 (m, 2H)2.24-2.43 (m, 2H) 4.24 (dd, J=1.3, 5.8 Hz, 2H) 4.64-4.82 (m, 1H)5.11-5.38 (m, 1H) 10.23-10.35 (m, 1H)

Method 2

65.2a) 1-Cyclohexyl-3-cyclopentyl-2,4,6(1H,3H,5H)-pyrimidinetrione.Cyclohexyl isocyanate (14.7 g, 117.34 mmoles) in dichloromethane (500mL) under argon was treated with a solution of cyclopentylamine (11.58mL, 117.34 mmoles) in dichloromethane (300 mL) and stirred overnight toleave a thick suspension of the urea. Malonyl dichloride (12.55 mL, 129mmoles) in dichloromethane (200 mL) was added and the mixture was heatedunder gentle reflux for 3.5 hours. The mixture was washed with 1 molarhydrochloric acid (×2) dried and evaporated. Crystallization fromethanol and flash chromatography of the liquors (hexane to ethylacetate) gave the title compound (18.9 g, 58%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 4.96-5.12 (m, 1H), 4.46 (tt, J=12.13, 3.54 Hz, 1H), 3.69(s, 2H), 2.15 (ddd, 2H), 1.67-2.00 (m, 8H), 1.41-1.66 (m, 5H), 1.27 (m,2H), 1.11 (m, 1H).

65.2b)N-[(1-Cyclohexyl-3-cyclopentyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.Ethyl isocyanatoacetate (8.33 mL, 74.3 mmoles) was added to a mixture of1-cyclohexyl-3-cyclopentyl-2,4,6(1H,3H,5H)-pyrimidinetrione (18.8 g,67.54 mmoles) and diisopropylethylamine (23.53 mL, 135.08 mmoles) indichloromethane (800 mL) and stirred for 2 hours. Reaction mixture froma prior run (approx 25% scale) was added. The combined reaction mixturewas washed with 2 molar hydrochloric acid (2×1.0 L) and evaporated. Theresidue was dissolved in ethanol (200 mL) and treated with 3.0 molarsodium hydroxide (100 mL). The mixture was stirred for 2 hours. Ethylacetate (500 mL) was added and the mixture acidified with 6 molarhydrochloric acid (200 mL), water (500 mL) was added and the layersseparated. The aqueous layer was extracted with ethyl acetate (500 mL)and the organic solution was washed with 1 molar hydrochloric acid. Theorganic solution was dried and evaporated to a solid residue whichrecrystallized from acetic acid (300 mL) to afford the title compound(15.5 g, 49%). Mp 222-224° C. 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.08 (s,1H), 10.17 (t, J=5.43 Hz, 1H), 5.08-5.33 (m, 1H), 4.63 (t, J=12.25 Hz,1H), 4.12 (d, J=5.81 Hz, 2H), 2.18-2.36 (m, 2H), 1.93-2.06 (m, 2H),1.69-1.91 (m, 6H), 1.46-1.68 (m, 5H), 1.28 (q, J=12.88 Hz, 2H), 1.12 (q,J=13.05 Hz, 1H).

Example 66

N-{[6-Hydroxy-1,3-bis(3-methylbutyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

66a) N,N′-Bis(3-methylbutyl)urea. Isoamylamine (1.4 mL, 12 mmoles) wasadded to a solution of [1,3]oxathiolo[4,5-b]pyridin-2-one (765 mg, 5.0mmoles) in ethyl acetate (15 mL). The mixture was stirred for 2 hours,the solid collected, washed with ethyl acetate and dried to give thetitle compound (1.1 g, 91%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.86(br. s, 2H), 3.20 (td, J=7.33, 5.81 Hz, 4H), 1.61-1.72 (m, J=13.39,6.69, 6.69, 6.69, 6.69 Hz, 2H), 1.40-1.48 (m, 4H), 0.93 (d, J=6.57 Hz,12H).

66b), 3-Bis(3-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione. Ethylmalonyl chloride (768 uL, 6.0 mmoles) was added to a solution ofN,N′-bis(3-methylbutyl)urea (1.1 g, 5.5 mmoles) in chloroform (70 mL)and the mixture was stirred at 70° C. for 2 hours. The mixture waswashed with 1 molar hydrochloric acid, dried and evaporated to giveethyl3-((3-methylbutyl){[(3-methylbutyl)amino]carbonyl}amino)-3-oxopropanoate.The intermediate was dissolved in ethanol (30 mL), DBU (900 uL, 6mmoles) and heated to 70° C. for 5 minutes. The mixture was cooled,diluted with ethyl acetate and washed with 1 molar hydrochloric acid,dried and evaporated to give the title compound (1.2 g, 81%). 1H NMR(400 MHz, DMSO-d₆) δ ppm 3.65-3.78 (m, 3H), 1.56 (dt, J=20.02, 13.33,6.57 Hz, 1H), 1.32-1.44 (m, 2H), 0.90 (d, J=6.57 Hz, 6H).

66c)-{[6-Hydroxy-1,3-bis(3-methylbutyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of 1,3-bis(3-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(1.2 g, 4.47 mmoles) and diisopropylethylamine (1.56 mL, 8.94 mmoles)was stirred in dichloromethane (30 mL) and treated with ethylisocyanatoacetate (501 uL, 4.47 mmoles). The mixture was stirred for 5hours, washed with 1 molar hydrochloric acid (×2), evaporated, taken upin ethanol-6 molar sodium hydroxide and stirred overnight. The mixturewas acidified and extracted into ethyl acetate (×2). The extracts werewashed with 1 molar hydrochloric acid evaporated, dried and evaporated.The title compound was recrystallized from acetic acid (430 mg, 26%). 1HNMR (400 MHz, DMSO-d₆) δ ppm 13.09 (br. s, 1H), 10.11 (s, 1H), 4.09-4.16(m, 2H), 3.77-3.86 (m, 4H), 1.51-1.62 (dt, J=13.29, 6.59, 6.59, 6.59,6.59 Hz, 2H), 1.42 (q, J=7.07 Hz, 4H), 0.91 (d, J=6.57 Hz, 12H).

Example 67

N-[(6-Hydroxy-1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

67a)1,3-Bis{[2-(methyloxy)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione.2-Methoxybenzyl isocyanate (923 uL, 6.0 mmoles) was added to a solutionof 2-methoxybenzylamine (775 uL, 6.0 mmoles) in chloroform (100 mL) andthe mixture stirred for 1 hour. Ethyl malonyl chloride (768 uL, 6.0mmoles) was added and the mixture was heated to 70° C. for 2 hours. DBU(1.0 mL) was added and the mixture was heated for a further 1 hour. Themixture was cooled and washed with 1 molar hydrochloric acid (×2), driedand evaporated. The title compound was obtained as a solid bytrituration in diethyl ether (1.65 g, 75 1H NMR (400 MHz, DMSO-d₆) δ ppm7.22 (t, 2H), 7.15 (d, J=7.58 Hz, 2H), 6.98 (d, J=7.58 Hz, 2H), 6.86 (t,2H), 4.88 (s, 4H), 3.81 (s, 6H), 3.79-3.80 (s, 2H).

67b)N-[(6-hydroxy-1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.A mixture of1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione(1.64 g, 4.45 mmoles) and diisopropylethylamine (1.56 mL, 8.94 mmoles)was stirred in dichloromethane (30 mL) and treated with ethylisocyanatoacetate (500 uL, 4.45 mmoles). The mixture was stirred for 5hours, washed with 1 molar hydrochloric acid (×2), evaporated, taken upin ethanol-6 molar sodium hydroxide and stirred overnight. The mixturewas acidified and extracted into ethyl acetate (×2). The extracts werewashed with 1 molar hydrochloric acid evaporated, dried and evaporated.The title compound was recrystallized from acetic acid (1.0 g, 48%). 1HNMR (400 MHz, DMSO-d₆) δ ppm 12.51 (br. s., 1H), 10.11 (t, J=4.93 Hz,1H), 7.20-7.28 (m, 2H), 7.00 (d, J=7.83 Hz, 2H), 6.86-6.96 (m, 4H), 5.00(s, 4H), 4.10-4.18 (m, 2H), 3.82 (s, 6H).

Example 68

N-({1,3-Bis[(2-chlorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

68a) 1,3-Bis[(2-chlorophenyl)methyl]-2,4,6(1H,3H,5H)-pyrimidinetrione.2-Chlorobenzyl isocyanate (875 uL, 6.0 mmoles) was added to a solutionof 2-chlorobenzylamine (725 uL, 6.0 mmoles) in chloroform (100 mL) andthe mixture stirred for 1 hour. Ethyl malonyl chloride (768 uL, 6.0mmoles) was added and the mixture was heated to 70° C. for 2 hours. DBU(1.0 mL) was added and the mixture was heated for a further 1 hour. Themixture was cooled and washed with 1 molar hydrochloric acid (×2), driedand evaporated to an oil (2.0 g, 88%). 1H NMR (400 MHz, DMSO-d₆) δ ppm7.45-7.49 (m, 2H), 7.40-7.45 (m, 2H), 7.28-7.32 (m, 4H), 4.98 (s, 4H),4.02 (s, 2H).

68b)N-({1,3-Bis[(2-chlorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine.A mixture of1,3-bis[(2-chlorophenyl)methyl]-2,4,6(1H,3H,5H)-pyrimidinetrione (2.0 g,5.3 mmoles) and diisopropylethylamine (1.85 mL, 10.6 mmoles) was stirredin dichloromethane (35 mL) and treated with ethyl isocyanatoacetate (594uL, 5.3 mmoles). The mixture was stirred for 5 hours, washed with 1molar hydrochloric acid (×2), evaporated, taken up in ethanol-6 molarsodium hydroxide and stirred overnight. The mixture was acidified andextracted into ethyl acetate (×2). The extracts were washed with 1 molarhydrochloric acid evaporated, dried and evaporated. The title compoundwas recrystallized from acetic acid (1.59 g, 62%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.06 (br. s., 1H), 10.13 (s, 1H), 7.41-7.60 (m, 2H),7.30 (dd, J=5.81, 3.28 Hz, 4H), 7.21 (dd, J=5.31, 3.79 Hz, 2H), 5.09 (s,4H), 4.15 (s, 2H).

Example 69

N-[(1,3-Dihexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Hexyl isocyanate (728 uL, 5.0 mmoles) was added to a solution ofn-hexylamine (660 uL, 5.0 mmoles) in dichloromethane (100 mL) and themixture stirred for 1 hour. Malonyl dichloride (486 uL, 5.0 mmoles) wasadded and the mixture was heated to gentle reflux for 1 hour. Themixture was washed with 1 molar hydrochloric acid (×2), dried andevaporated. The residue was redissolved in dichloromethane (50 mL) anddiisopropylethylamine (1.73 mL, 10 mmoles) and the mixture was treatedwith ethyl isocyanatoacetate (561 uL, 5.0 mmoles). After stirringovernight the mixture was washed with 1 molar hydrochloric acid, driedand evaporated. The residue was dissolved in ethanol (5 mL) and treatedwith 6 molar sodium hydroxide (2.0 mL). The mixture was stirred for 1hour, acidified and extracted into ethyl acetate. The organic solutionwas washed with 1 molar hydrochloric acid, dried and evaporated. Thecrude product was slurried in hexane to afford the title compound (890mg, 45%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (br. s, 1H), 10.10 (t,J=4.80 Hz, 1H), 4.13 (d, J=5.81 Hz, 2H), 3.75-3.84 (m, 4H), 1.53 (s,4H), 1.26 (s, 12H), 0.82-0.90 (m, 6H).

Example 70

N-{[1-Cyclohexyl-6-hydroxy-3-(2-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Using 2-methylcyclohexylamine in place of 4-methylcyclohexylamine, thetitle compound was prepared in 19% yield (390 mg) following theprocedures described in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm0.68-0.84 (m, 3H) 1.14-1.43 (m, 8H) 1.53-1.76 (m, 5H) 1.76-1.90 (m, 4H)2.14-2.43 (m, 3H) 4.18-4.27 (m, 2H) 4.38-4.54 (m, 1H) 4.62-4.87 (m, 2H)10.21-10.43 (m, 1H)

Example 71

N-{[1-Cyclohexyl-6-hydroxy-3-(2-naphthalenyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Using 2-aminonaphthalene in place of 4-methylcyclohexylamine, the titlecompound was prepared in 0.6% yield (12.9 mg) following the proceduresdescribed in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm 1.04-1.19 (m, 1H)1.27-1.46 (m, 2H) 1.57-1.93 (m, 6H) 2.26-2.48 (m, 2H) 4.06-4.21 (m, 1H)4.23 (d, J=5.6 Hz, 1H) 4.72-4.91 (m, 1H) 7.39 (dd, J=1.0, 7.3 Hz, 1H)7.47-7.65 (m, 4H) 7.84-8.03 (m, 2H) 10.21 (t, J=5.6 Hz, 1H)

Example 72

N-[(1-Cyclohexyl-3-hexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Cyclohexyl isocyanate (635 uL, 5.0 mmoles) was added to a solution ofn-hexylamine (660 uL, 5.0 mmoles) in dichloromethane (100 mL) and themixture stirred for 1 hour. Malonyl dichloride (486 uL, 5.0 mmoles) wasadded and the mixture was heated to gentle reflux for 1 hour. Themixture was washed with 1 molar hydrochloric acid (×2), dried andevaporated. The residue was redissolved in dichloromethane (50 mL) anddiisopropylethylamine (1.73 mL, 10 mmoles) and the mixture was treatedwith ethyl isocyanatoacetate (561 uL, 5.0 mmoles). After stirringovernight the mixture was washed with 1 molar hydrochloric acid, driedand evaporated. The residue was dissolved in ethanol (5 mL) and treatedwith 6 molar sodium hydroxide (2.0 mL). The mixture was stirred for 1hour, acidified and extracted into ethyl acetate. The organic solutionwas washed with 1 molar hydrochloric acid, dried and evaporated to abrown oil. The crude material was stood in a freezer overnight in hexaneto afford some solid. The liquors were concentrated and purified bypreparative HPLC (acetonitrile-water-0.1% TFA) to give additionalmaterial which was combined with the previously obtained solid andrecrystallized from ethanol-water to give the title compound (480 mg,24%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.09 (br. s., 1H), 10.15 (t,J=5.56 Hz, 1H), 4.53-4.73 (m, 1H), 4.05-4.18 (m, 2H), 3.78 (t, 2H),2.16-2.36 (m, 2H), 1.79 (d, J=12.38 Hz, 2H), 1.42-1.71 (m, 5H), 1.26 (s,8H), 1.03-1.19 (m, 1H), 0.79-0.92 (m, 3H).

Example 73

N-[(1,3-Dicycloheptyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Using cycloheptylamine in place of 4-methylcyclohexylamine andcycloheptylisocyanate in place of cyclohexylisocyanate, the titlecompound was prepared in 7% yield (142.6 mg) following the proceduresdescribed in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm 1.19-1.36 (m, 2H)1.37-1.92 (m, 17H) 2.20-2.42 (m, 6H) 4.15 (d, J=5.8 Hz, 2H) 4.69-5.03(m, 3H) 10.20-10.46 (m, 1H)

Example 74

N-[(1,3-Dicyclopentyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Method 1

Using cyclopentylamine in place of 4-methylcyclohexylamine andcyclopentylisocyanate in place of cyclohexylisocyanate, the titlecompound was prepared in 14% yield (263 mg) following the proceduresdescribed in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm 1.50-1.66 (m, 4H)1.75-1.88 (m, 4H) 1.88-2.00 (m, 4H) 2.01-2.16 (m, 4H) 2.56-2.71 (m, 1H)3.06-3.27 (m, 1H) 4.14 (d, J=5.6 Hz, 2H) 5.12-5.40 (m, 2H) 10.28-10.41(m, 1H)

Example 75

N-{[1-Cyclohexyl-3-(2,3-dimethylcyclohexyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Using 2,3-dimethylcyclohexylamine in place of 4-methylcyclohexylamine,the title compound was prepared in 5% yield (85 mg) following theprocedures described in example 54. LC/MS m/z 422 (M+H⁺).

Example 76

4-[5-{[(Carboxymethyl)amino]carbonyl}-3-cyclohexyl-4-hydroxy-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]cyclohexanecarboxylicAcid

Using 4-aminocyclohexanecarboxylic acid in place of4-methylcyclohexylamine, the title compound was prepared in 16% yield(151 mg) following the procedures described in example 54. LC/MS m/z 438(M+H⁺).

Example 77

N-{[1-Cyclohexyl-3-(4-ethylcyclohexyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Using 4-ethylcyclohexylamine in place of 4-methylcyclohexylamine, thetitle compound was prepared in 20% yield (185 mg) following theprocedures described in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm0.85-0.96 (m, 3H) 1.10-1.40 (m, 8H) 1.53-1.72 (m, 6H) 1.73-1.89 (m, 3H)2.19-2.61 (m, 3H) 3.85-4.04 (m, 1H) 4.09-4.34 (m, 2H) 4.59-4.85 (m, 2H)5.07-5.32 (m, 2H) 10.30-10.426 (m, 1H).

Example 78

cis-4-[3-Cyclohexyl-5-({[2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-4-hydroxy-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]cyclohexanecarboxylicAcid

Using cis-4-aminocyclohexanecarboxylic acid 1 in place of4-methylcyclohexylamine, the title compound was prepared in 9% yield(114 mg) following the procedures described in example 54. LC/MS m/z 466(M+H⁺).

Example 79

N-{[1-Cyclohexyl-6-hydroxy-3-(1-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Using 1-amino-1-methylcyclohexane in place of 4-methylcyclohexylamine,the title compound was prepared in 18% yield (595 mg) following theprocedures described in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm0.97-1.18 (m, 3H) 1.19-1.44 (m, 9H) 1.46-1.74 (m, 5H) 1.77-1.99 (m, 4H)2.22-2.40 (m, 2H) 3.11-3.30 (m, 2H) 4.07-4.37 (m, 2H) 4.50-4.78 (m, 1H)10.15-10.35 (m, 1H)

Example 80

3-[5-{[(Carboxymethyl)amino]carbonyl}-3-cyclohexyl-4-hydroxy-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]cyclohexanecarboxylicAcid

Using 3-aminocyclohexanecarboxylic acid in place of4-methylcyclohexylamine, the title compound was prepared in 18% yield(184 mg) following the procedures described in example 54. LC/MS m/z 438(M+H⁺).

Example 81

N-{[1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-(2-oxo-2-phenylethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

A mixture of ethylN-[(3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(300 mg, 0.88 mmoles), 2-bromoacetophenone (350 mg, 1.76 mmoles) andpotassium carbonate (243 mg, 1.76 mmoles) in DMF (4 mL) was heated in amicrowave synthesiser at 100° C. for 15 minutes, then cooled andfiltered. The residue was washed with dichloromethane (3×3 mL) and thecombined filtrate was evaporated and purified by flash chromatography(ethyl acetate-hexane) to obtain the desired crude ester. The ester wasdissolved in ethanol (3 mL) and 1M aqueous NaOH (1 mL) and the solutionstirred for 2 hours, then neutralized by addition of 1M aqueous HCl. Thesolid was collected, washed with water (3×4 mL) and dried under vacuumovernight to give the title compound (51 mg, 20%). 1H NMR (400 MHz,CDCl₃) δ ppm 1.10-1.27 (m, 1H) 1.27-1.45 (m, 2H) 1.58-1.77 (m, 3H)1.77-1.91 (m, 2H) 2.24-2.43 (m, 2H) 3.56-5.09 (br s, 2H), 4.19-4.26 (m,2H) 4.62-4.85 (m, 1H) 5.31-5.41 (m, 2H) 7.45-7.55 (m, 2H) 7.58-7.66 (m,1H) 7.97-8.03 (m, 2H) 10.04-10.42 (m, 1H)

Example 82

N-[(1-Cyclohexyl-6-hydroxy-3-{2-[4-(methyloxy)phenyl]-2-oxoethyl}-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Using 2-bromo-4′-methoxyacetophenone in place of 2-bromoacetophenone,the title compound was prepared in 48% yield (196 mg) following theprocedures described in example 81. LC/MS m/z 460 (M+H⁺).

Example 83

N-({1-Cyclohexyl-6-hydroxy-3-[2-(4-methylphenyl)-2-oxoethyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

Using 2-bromo-4′-methylacetophenone in place of 2-bromoacetophenone, thetitle compound was prepared in 61% yield (241 mg) following theprocedures described in example 81. 1H NMR (400 MHz, CDCl₃) δ ppm1.10-1.43 (m, 4H) 1.57-1.75 (m, 4H) 1.77-1.90 (m, 2H) 2.21-2.52 (m, 5H)4.11-4.29 (m, 2H) 4.64-4.85 (m, 1H) 5.26-5.39 (m, 2H) 7.20-7.35 (m, 2H)7.89 (d, J=8.3 Hz, 2H) 10.02-10.41 (m, 1H)

Example 84

N-{[1-Cyclohexyl-3-(3,3-dimethyl-2-oxobutyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Using 1-bromopinacolone in place of 2-bromoacetophenone, the titlecompound was prepared in 31% yield (114 mg) following the proceduresdescribed in example 81. 1H NMR (400 MHz, CDCl₃) δ ppm 1.01-1.45 (m, 5H)1.26 (s, 9H) 1.57-1.76 (m, 3H) 1.76-1.91 (m, 2H) 2.22-2.43 (m, 2H)4.15-4.30 (m, 2H) 4.62-4.79 (m, 1H) 4.82-4.97 (m, 2H) 9.97-10.39 (m, 1H)

Example 85

N-({1-Cyclohexyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

Using 2-bromo-4′-fluoroacetophenone in place of 2-bromoacetophenone, thetitle compound was prepared in 69% yield (275 mg) following theprocedures described in example 81. 1H NMR (400 MHz, CDCl₃) δ ppm1.06-1.43 (m, 5H) 1.55-1.76 (m, 3H) 1.76-1.93 (m, 2H) 2.23-2.43 (m, 2H)4.09-4.33 (m, 2H) 4.65-4.84 (m, 1H) 5.28-5.38 (m, 2H) 7.13-7.23 (m, 2H)7.99-8.08 (m, 2H) 10.01-10.52 (m, 1H)

Example 86

N-({3-[2-(4-Cyanophenyl)-2-oxoethyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

Using 2-bromo-4′-cyanoacetophenone in place of 2-bromoacetophenone, thetitle compound was prepared in 65% yield (259 mg) following theprocedures described in example 81. 1H NMR (400 MHz, CDCl₃) δ ppm1.05-1.45 (m, 5H) 1.59-1.77 (m, 3H) 1.77-1.91 (m, 2H) 2.21-2.40 (m, 2H)4.18-4.29 (m, 2H) 4.64-4.83 (m, 1H) 5.29-5.41 (m, 2H) 7.79-7.85 (m, 2H)8.09 (d, J=8.6 Hz, 2H) 9.99-10.45 (m, 1H)

Example 87

N-({3-[2-(1-Benzofuran-2-yl)-2-oxoethyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

Using 1-(1-benzofuran-2-yl)-2-bromoethan-1-one in place of2-bromoacetophenone, the title compound was prepared in 44% yield (183mg) following the procedures described in example 81. 1H NMR (400 MHz,CDCl₃) δ ppm 1.04-1.44 (m, 5H) 1.59-1.77 (m, 3H) 1.77-1.91 (m, 2H)2.25-2.43 (m, 2H) 4.16-4.28 (m, 2H) 4.65-4.84 (m, 1H) 5.30-5.40 (m, 2H)7.30-7.38 (m, 1H) 7.46-7.56 (m, 1H) 7.56-7.67 (m, 2H) 7.69-7.78 (m, 1H)10.02-10.45 (m, 1H)

Example 88

N-{[3-Cyclohexyl-6-hydroxy-1-(1-naphthalenyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Using 1-aminonaphthalene in place of 4-methylcyclohexylamine, the titlecompound was prepared in 20% yield (257 mg) following the proceduresdescribed in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm 1.07-1.43 (m, 4H)1.56-1.90 (m, 5H) 2.27-2.48 (m, 2H) 4.05-4.19 (m, 2H) 4.23 (d, J=5.8 Hz,1H) 4.71-4.92 (m, 1H) 7.37-7.46 (m, 1H) 7.48-7.61 (m, 4H) 7.87-8.00 (m,2H) 9.99-10.46 (m, 1H)

Example 89

N-{[3-Cyclohexyl-1-(4,4-dimethylcyclohexyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Using 4,4-dimethylcyclohexylamine in place of 4-methylcyclohexylamine,the title compound was prepared in 3% yield (45 mg) following theprocedures described in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm 0.93(s, 3H) 1.02 (s, 3H) 1.14-1.53 (m, 11H) 1.56-1.72 (m, 3H) 1.77-1.89 (m,2H) 2.26-2.43 (m, 2H) 2.45-2.65 (m, 2H) 4.15-4.32 (m, 2H) 4.57-4.84 (m,2H) 10.20-10.40 (m, 1H)

Example 90

N-({1-Cyclohexyl-3-[(2,3-difluorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles)and 2,3-difluorobenzyl bromide (255 uL, 2.0 mmoles) in dimethylacetamide(5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture waspoured into 1 molar hydrochloric acid and extracted with ethyl acetate(×2). The combined organic solutions were washed with 1 molarhydrochloric acid and evaporated. The residue was purified by flashchromatography (10-50% ethyl acetate in hexane), the required fractionsevaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxidesolution (3.0 mL) added. The mixture was stirred overnight, acidifiedand extracted with ethyl acetate (×2), the combined extracts washed with1 molar hydrochloric acid, dried and evaporated. Recrystallization fromethanol-water gave the title compound (140 mg, 32%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.10 (br. s., 1H), 10.11 (br. s., 1H), 7.25-7.43 (m,1H), 7.08-7.23 (m, 1H), 7.03 (t, J=7.07 Hz, 1H), 5.08 (s, 2H), 4.55-4.73(m, 1H), 4.13 (d, J=5.81 Hz, 2H), 2.12-2.35 (m, 2H), 1.78 (d, J=12.63Hz, 2H), 1.63 (s, 3H), 1.20-1.38 (m, 2H), 1.02-1.18 (m, 1H)

Example 91

EthylN-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonothioyl]glycinate

A mixture of 1,3-dicyclohexyl-2,4,6(1H,3H,5H)-pyrimidinetrione (660 mg,2.25 mmoles), diisopropylethylamine (780 uL, 4.5 mmoles) and ethylisocyanatoacetate (340 uL, 2.75 mmoles) in chloroform (20 mL) wasstirred for 6 hours. The mixture was washed with 1 molar hydrochloricacid (×2), dried and evaporated. The solid residue was purified by flashchromatography (0-20% ethyl acetate in hexane) and crystallization fromethanol to give the title compound (250 mg, 25%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 12.57 (t, J=5.18 Hz, 1H), 4.69 (t, 2H), 4.44 (d, J=5.31Hz, 2H), 4.17 (q, J=7.24 Hz, 2H), 2.25 (q, 4H), 1.79 (d, J=12.88 Hz,4H), 1.55-1.72 (m, 6H), 1.24-1.38 (m, 4H), 1.22 (t, J=7.07 Hz, 3H), 1.12(q, J=12.88 Hz, 2H).

Example 92

N-[(1,3-Dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonothioyl]glycine

A mixture of 1,3-dicyclohexyl-2,4,6(1H,3H,5H)-pyrimidinetrione (660 mg,2.25 mmoles), diisopropylethylamine (780 uL, 4.5 mmoles) and ethylisothiocyanatoacetate (340 uL, 2.75 mmoles) in chloroform (20 mL) wasstirred overnight. The mixture was washed with 1 molar hydrochloric acid(×2), dried and evaporated. The solid residue was purified by flashchromatography (dichloromethane) and the fractions evaporated, dissolvedin ethanol (5 mL, some heating) and treated with 1 molar sodiumhydroxide (3 mL). The mixture was stirred for 30 minutes and acidifiedto give a solid which recrystallized from ethanol-water to give thetitle compound (135 mg, 15%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.16 (s,1H), 12.54 (t, J=4.80 Hz, 1H), 4.69 (t, J=12.00 Hz, 2H), 4.35 (d, J=5.05Hz, 2H), 2.25 (q, 4H), 1.79 (d, J=12.38 Hz, 4H), 1.63 (d, J=12.38 Hz,6H), 1.29 (q, 4H), 1.13 (q, 2H).

Example 93

6-[5-{[(Carboxymethyl)amino]carbonyl}-3-cyclohexyl-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]hexanoicAcid

93a) Ethyl6-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)hexanoate.Ethyl isocyanatohexanoate (790 mg, 4.26 mmoles) and cyclohexylamine (490uL, 4.26 mmoles) were stirred together in dichloromethane (100 mL) for 2hours. Malonyl dichloride (414 uL, 4.26 mmoles) was added and themixture was heated under gentle reflux for 2 hours. The mixture waspurified by flash chromatography (dichloromethane to 5% methanol indichloromethane) to give the title compound (1.07 g, 71%). 1H NMR (400MHz, CHLOROFORM-d) δ ppm 4.56-4.67 (m, 1H), 4.62 (tt, J=12.25, 3.79 Hz,1H), 4.13 (q, J=7.24 Hz, 2H), 3.85 (t, 2H), 2.31 (t, 2H), 2.26 (dq, 2H),1.85 (d, J=13.39 Hz, 2H), 1.57-1.73 (m, 7H), 1.29-1.43 (m, 4H), 1.26 (t,J=7.07 Hz, 3H), 1.06-1.24 (m, 2H).

93b)6-[5-{[(Carboxymethyl)amino]carbonyl}-3-cyclohexyl-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]hexanoicacid. A mixture of ethyl6-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)hexanoate (330mg, 0.936 mmoles) and diisopropylethylamine (324 uL, 1.87 mmoles) inchloroform (30 mL) was treated with ethyl isocyanatoacetate (126 uL,1.12 mmoles) and stirred overnight. The mixture was washed with 1 molarhydrochloric acid (×2), dried and evaporated. The residue was taken upin ethanol and treated with 1 molar sodium hydroxide (2 mL) and stirredfor 1 hour. The mixture was acidified and extracted into ethyl acetate.The organic solution was washed with 1 molar hydrochloric acid, driedand evaporated. Crystallization from acetic acid afforded the titlecompound (160 mg, 40%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.06 (br. s.,1H), 12.08 (br. s., 1H), 10.15 (t, J=5.81 Hz, 1H), 4.63 (t, J=9.22 Hz,1H), 4.12 (d, J=5.81 Hz, 2H), 3.66-3.87 (m, 2H), 2.26 (d, J=11.37 Hz,2H), 2.20 (t, J=7.33 Hz, 2H), 1.79 (d, J=12.88 Hz, 2H), 1.57-1.68 (m,3H), 1.46-1.57 (m, 4H), 1.21-1.35 (m, 4H), 1.04-1.19 (m, 1H).

Example 94

6-[5-{[(Carboxymethyl)amino]carbonothioyl}-3-cyclohexyl-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]hexanoicAcid

A mixture of ethyl6-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)hexanoate (330mg, 0.94 mmoles), diisopropylethylamine (324 uL, 1.87 mmoles) and ethylisothiocyanatoacetate (139 uL, 1.12 mmoles) in chloroform (20 mL) wasstirred for 7 days. The mixture was washed with 1 molar hydrochloricacid (×2), dried and evaporated. The residue was purified by flashchromatography (hexane-20% ethyl acetate in hexane) to give the titlecompound as a clear oil (250 mg, 60%). The diester was dissolved inethanol (3 mL) and treated with 1 molar sodium hydroxide (2 mL). Themixture was stirred overnight, taken up in ethyl acetate and washed with1 molar hydrochloric acid (×2), dried and evaporated. Crystallizationfrom acetic acid afforded the title compound (160 mg, 40%). 1H NMR (400MHz, DMSO-d₆) δ ppm 13.13 (br s, 1H), 12.50 (s, 1H), 12.03 (br s, 1H),4.71 (m, 1H), 4.35 (d, J=5.05 Hz, 2H), 3.84 (t, J=7.20 Hz, 2H),2.10-2.38 (m, 4H), 1.80 (d, J=12.63 Hz, 2H), 1.42-1.71 (m, 7H),1.21-1.42 (m, 4H), 1.01-1.22 (m, 1H).

Example 95

N-({1-Cyclohexyl-3-[(3,4-dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles)and 3,4-dichlorobenzyl bromide (480 uL, 2.0 mmoles) in dimethylacetamide(5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture waspoured into 1 molar hydrochloric acid and extracted with ethyl acetate(×2). The combined organic solutions were washed with 1 molarhydrochloric acid and evaporated. The residue was purified by flashchromatography (10-50% ethyl acetate in hexane), the required fractionsevaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxidesolution (3.0 mL) added. The mixture was stirred overnight, acidifiedand extracted with ethyl acetate (×2), the combined extracts washed with1 molar hydrochloric acid, dried and evaporated. Recrystallization fromethanol-water gave the title compound (154 mg, 33%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.11 (br. s., 1H), 10.12 (br. s., 1H), 7.58 (dd, J=5.05,3.03 Hz, 2H), 7.29 (dd, J=8.34, 2.02 Hz, 1H), 4.97 (s, 2H), 4.62 (t,J=12.00 Hz, 1H), 4.13 (d, J=5.81 Hz, 2H), 2.24 (q, 2H), 1.78 (d, J=12.63Hz, 2H), 1.63 (s, 3H), 1.27 (q, J=12.88 Hz, 2H), 1.11 (q, 1H)

Example 96

N-[(1-Cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

EthylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(270 mg, 0.80 mmol)) was dissolved in ethanol (2 mL) and 1M aqueous NaOHsolution was added. The solution was stirred one hour at roomtemperature, then neutralized by addition of 1M aqueous HCl. Theresulting solid was collected, washed with water, and dried under vacuumovernight to give the title compound (208 mg, 84%). LC/MS m/z 312(M+H⁺).

Example 97

N-({3-Cyclohexyl-6-hydroxy-1-[trans-4-(methyloxy)cyclohexyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

Using trans-4-(methyloxy)cyclohexanamine hydrochloride in place of4-methylcyclohexylamine, the title compound was prepared in 11% yield(541.6 mg) following the procedures described in example 54. 1H NMR (400MHz, CDCl₃) δ ppm 1.12-1.50 (m, 6H) 1.56-1.77 (m, 6H) 1.78-1.90 (m, 2H)2.09-2.22 (m, 2H) 2.25-2.55 (m, 4H) 3.18-3.31 (m, 1H) 3.37 (s, 3H) 4.22(d, J=5.3 Hz, 2H) 4.62-4.89 (m, 2H) 10.22-10.41 (m, 1H)

Example 98

N-({1-[1,1′-Bi(cyclohexyl)-4-yl]-3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

Using 1,1′-bi(cyclohexyl)-4-amine hydrochloride in place of4-methylcyclohexylamine, the title compound was prepared in 19% yield(84 mg) following the procedures described in example 54. 1H NMR (400MHz, CDCl₃) δ ppm 0.88-1.43 (m, 13H) 1.56-1.76 (m, 11H) 1.76-1.91 (m,4H) 2.26-2.43 (m, 4H) 4.24 (d, J=5.8 Hz, 2H) 4.59-4.82 (m, 2H)10.24-10.38 (m, 1H)

Example 99

N-{[6-Hydroxy-2,4-dioxo-1,3-bis(1-propylbutyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

99a) N,N′-Bis(1-propylbutyl)urea. A mixture of carbonyldiimidazole (3.0g, 18.5 mmoles) and 4-heptylamine (6.0 mL, 40 mmoles) indimethylformamide (25 mL) was heated at 70° C. for 3 hours. The mixturewas cooled and partitioned between ethyl acetate and 1 molarhydrochloric acid. The aqueous was extracted with ethyl acetate and thecombined extracts washed with 1 molar hydrochloric acid, dried andevaporated to a solid (4.18 g, 88%). 1H NMR (400 MHz, DMSO-d₆) δ ppm5.34 (d, J=8.59 Hz, 2H), 1.12-1.38 (m, 16H), 0.85 (t, J=6.19 Hz, 12H).

99b) 1,3-Bis(1-propylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione.N,N′-bis(1-propylbutyl)urea (1.87 g, 7.29 mmoles) in chloroform (70 mL)was treated with malonyl dichloride (851 uL, 8.75 mmoles) and heated at70° C. for 3 hours. The mixture was washed with 1 molar hydrochloricacid (×2), dried and evaporated. Flash chromatography (hexane-50% ethylacetate in hexane) gave the title compound (660 mg, 28%). 1H NMR (400MHz, CHLOROFORM-d) δ ppm 4.78 (s, 2H), 3.61 (s, 2H), 1.94-2.04 (m, 4H),1.58-1.67 (m, 4H), 1.17-1.28 (m, 8H), 0.90 (t, J=7.33 Hz, 12H)

99c)N-{[1,3-Bis(1-ethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of 1,3-bis(1-ethylpropyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(660 mg, 2.0 mmoles) and diisopropylethylamine (690 uL, 4.0 mmoles) indichloromethane (50 mL) was treated with ethyl isocyanatoacetate (270uL, 2.4 mmoles) and stirred overnight. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated. The residue wasdissolved in ethanol (6 mL) and treated with 6 molar sodium hydroxide(4.0 mL). The mixture was stirred for 72 hour, acidified and extractedwith ethyl acetate (×2), dried and evaporated. The residue was stored at−10° C. overnight to crystallize. The solid produced was slurried inhexane, collected and washed with hexane to give the title compound(310, 36%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.09 (s, 1H), 10.19 (d,J=21.47 Hz, 1H), 4.82 (s, 2H), 4.12 (d, J=3.54 Hz, 2H), 2.02 (s, 4H),1.58 (s, 4H), 1.16 (s, 8H), 0.84 (t, J=7.33 Hz, 12H)

Example 100

N-({3-(2-Cyclopropylethyl)-6-hydroxy-1-[3-(methyloxy)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

100a)1-(2-Cyclopropylethyl)-3-{[3-(methyloxy)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione.Cyclopropylethylamine hydrochloride (2.0 g, 16.44 mmoles) indichloromethane (60 mL) was treated with diisopropylethylamine (2.84 mL,16.44 mmoles) followed by 3-methoxyphenyl isocyanate (2.12 mL, 16.44mmoles). The mixture was stirred for 1 hour, malonyl dichloride (1.92mL, 19.73 mmoles) was added and the mixture heated under gentle refluxfor 4 hours. The mixture was washed with 1 molar hydrochloric acid andpurified by flash chromatography (hexane to 30% ethyl acetate in hexane)to give the title compound which was obtained as a solid fromhexane-diethyl ether (2.12 g, 42%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.37(t, J=8.21 Hz, 1H), 6.94-7.12 (m, 1H), 6.69-6.88 (m, 2H), 3.86 (s, 2H),3.78-3.85 (m, 2H), 3.76 (s, 3H), 1.43 (q, J=7.07 Hz, 2H), 0.69 (dt, 1H),0.29-0.47 (m, 2H), −0.09-0.12 (m, 2H)

100b)N-({3-(2-Cyclopropylethyl)-6-hydroxy-1-[3-(methyloxy)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine.A mixture1-(2-cyclopropylethyl)-3-{[3-(methyloxy)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione(2.12 g, 7.0 mmole) and diisopropylethylamine (2.42 mL, 14.0 mmoles) indichloromethane (80 mL) was treated with ethyl isocyanatoacetate (942uL, 8.4 mmoles) and stirred for 72 hours. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated. The residue wasdissolved in ethanol (10 mL) and treated with 6 molar sodium hydroxide(6.0 mL). The mixture was stirred for 2 hours, acidified and extractedwith ethyl acetate (×2), dried and evaporated. The residue was purifiedby flash chromatography (1.0% methanol-0.1% acetic acid indichloromethane to 3.0% methanol-0.1% acetic acid in dichloromethane) togive the title compound (1.4 g, 50%). 1H NMR (400 MHz, DMSO-d₆) δ ppm13.12 (br. s, 1H), 10.04 (s, 1H), 8.35 (s, 1H), 8.32 (d, J=8.08 Hz, 1H),7.76-7.87 (m, 2H), 4.14 (d, J=5.56 Hz, 2H), 3.87-3.97 (m, 2H), 2.50 (s,3H), 1.50 (q, J=7.16 Hz, 2H), 0.66-0.76 (m, 1H), 0.37-0.46 (m, 2H), 0.05(q, J=4.80 Hz, 2H)

Example 101

N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(4-phenylcyclohexyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Using 4-phenylcyclohexylamine in place of 4-methylcyclohexylamine, thetitle compound was prepared in 29% yield (173 mg) following theprocedures described in example 54. 1H NMR (400 MHz, CDCl₃) δ ppm1.16-1.44 (m, 4H) 1.56-1.91 (m, 8H) 1.95-2.07 (m, 3H) 2.27-2.43 (m, 2H)2.51-2.68 (m, 4H) 4.26 (d, J=5.6 Hz, 2H) 4.65-4.96 (m, 2H) 7.15-7.25 (m,3H) 7.27-7.35 (m, 2H) 10.27-10.38 (m, 1H)

Example 102

N-({1-Cyclohexyl-3-[(3,4-difluorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles)and 3,4-difluorobenzyl bromide (256 uL, 2.0 mmoles) in dimethylacetamide(5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture waspoured into 1 molar hydrochloric acid and extracted with ethyl acetate(×2). The combined organic solutions were washed with 1 molarhydrochloric acid and evaporated. The residue was purified by flashchromatography (10-50% ethyl acetate in hexane), the required fractionsevaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxidesolution (3.0 mL) added. The mixture was stirred overnight, acidifiedand extracted with ethyl acetate (×2), the combined extracts washed with1 molar hydrochloric acid, dried and evaporated. Recrystallization fromethanol-water gave the title compound (138 mg, 32%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.11 (br. s., 1H), 10.12 (br. s., 1H), 7.28-7.52 (m,2H), 7.05-7.23 (m, J=5.43, 3.16 Hz, 1H), 4.96 (s, 2H), 4.63 (t, J=12.00Hz, 1H), 4.13 (d, J=5.81 Hz, 2H), 2.25 (q, 2H), 1.78 (d, J=12.88 Hz,2H), 1.63 (s, 3H), 1.28 (q, J=12.97 Hz, 2H), 1.11 (q, 1H)

Example 103

N-({3-(2-Cyclopropylethyl)-6-hydroxy-1-[4-(methyloxy)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

103a)1-(2-Cyclopropylethyl)-3-{[4-(methyloxy)phenyl]methyl}-2,4,6(1H,3H5H)-pyrimidinetrione.Cyclopropylethylamine hydrochloride (1.62 g, 13.32 mmoles) in chloroform(80 mL) was treated with diisopropylethylamine (2.3 mL, 13.32 mmoles)followed by 4-methoxyphenyl isocyanate (1.73 mL, 13.32 mmoles). Themixture was stirred for 2 hours, malonyl dichloride (1.55 mL, 16.0mmoles) was added and the mixture heated at 43° C. for 4 hours. Themixture was washed with 1 molar hydrochloric acid and purified by flashchromatography (hexane to 35% ethyl acetate in hexane) to give the titlecompound which was obtained as a solid from hexane-diethyl ether (2.2 g,54%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.13 (d, 2H), 7.00 (d, J=9.09 Hz,2H), 3.85 (s, 2H), 3.80-3.84 (m, 2H), 3.79 (s, 3H), 1.42 (q, J=7.07 Hz,2H), 0.62-0.77 (m, 1H), 0.36-0.44 (m, 2H), −0.00-0.06 (m, 2H)

103b)N-({3-(2-Cyclopropylethyl)-6-hydroxy-1-[4-(methyloxy)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine.A mixture1-(2-cyclopropylethyl)-3-{[4-(methyloxy)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione(2.2 g, 7.27 mmole) and diisopropylethylamine (2.50 mL, 14.5 mmoles) indichloromethane (80 mL) was treated with ethyl isocyanatoacetate (979uL, 8.7 mmoles) and stirred overnight. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated. The residue wasdissolved in ethanol (6 mL) and treated with 6 molar sodium hydroxide(5.0 mL). The mixture was stirred for 2 hours, acidified and extractedwith ethyl acetate (×2), dried and evaporated. The residue was purifiedby flash chromatography (1.0% methanol-0.1% acetic acid indichloromethane to 3.0% methanol-0.1% acetic acid in dichloromethane) togive the title compound (1.3 g, 44%). 1H NMR (400 MHz, DMSO-d₆) δ ppm13.10 (s, 1H), 10.08 (s, 1H), 7.21 (d, J=5.31 Hz, 2H), 6.97-7.04 (m,2H), 4.13 (d, J=5.81 Hz, 2H), 3.89-3.97 (m, 2H), 3.80 (s, 3H), 1.48 (q,J=6.91 Hz, 2H), 0.64-0.74 (m, J=15.22, 12.25, 7.39, 5.05 Hz, 1H), 0.41(ddd, J=7.96, 5.68, 4.04 Hz, 2H), 0.02 (td, J=5.18, 4.29 Hz, 2H)

Example 104

N-{[3-(2-Cyclopropylethyl)-6-hydroxy-1-(3-nitrophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

104a)1-(2-Cyclopropylethyl)-3-(3-nitrophenyl)-2,4,6(1H,3H,5H)-pyrimidinetrione.Cyclopropylethylamine hydrochloride (1.62 g, 13.32 mmoles) in chloroform(80 mL) was treated with diisopropylethylamine (2.3 mL, 13.32 mmoles)followed by 3-nitrophenyl isocyanate (2.19 g, 13.32 mmoles). The mixturewas stirred for 2 hours, malonyl dichloride (1.55 mL, 16.0 mmoles) wasadded and the mixture heated at 43° C. for 4 hours. The mixture waswashed with 1 molar hydrochloric acid and purified by flashchromatography (hexane to 50% ethyl acetate in hexane) to give the titlecompound (1.66 g, 40%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.27-8.36 (m,1H), 8.22 (t, J=2.02 Hz, 1H), 7.80 (d, J=8.08 Hz, 1H), 7.71-7.77 (m,1H), 3.90 (s, 2H), 3.84 (t, 2H), 1.44 (q, J=7.16 Hz, 2H), 0.62-0.80 (m,1H), 0.31-0.47 (m, 2H), 0.05 (q, J=4.80 Hz, 2H)

104b)N-{[1-(2-Cyclopropylethyl)-6-hydroxy-3-(3-nitrophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture1-(2-cyclopropylethyl)-3-(3-nitrophenyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(1.66 g, 5.23 mmole) and diisopropylethylamine (1.80 mL, 10.5 mmoles) indichloromethane (80 mL) was treated with ethyl isocyanatoacetate (704uL, 6.27 mmoles) and stirred overnight. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated. The residue wasdissolved in ethanol (6 mL) and treated with 6 molar sodium hydroxide(5.0 mL). The mixture was stirred for 1 hour, acidified and extractedwith ethyl acetate (×2), dried and evaporated. A solid was obtained fromacetic acid-water, which was purified by trituration in boilingchloroform to give the title compound (800 mg, 37%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.12 (br. s, 1H), 10.03 (s, 1H), 8.35 (s, 1H), 8.32(ddd, J=8.40, 1.64, 1.33 Hz, 1H), 7.82-7.88 (m, 1H), 7.79 (t, J=8.08 Hz,1H), 4.14 (d, J=5.81 Hz, 2H), 3.88-3.97 (m, 2H), 1.50 (q, J=7.16 Hz,2H), 0.66-0.76 (m, 1H), 0.42 (ddd, J=7.96, 5.68, 4.04 Hz, 2H), 0.05 (td,J=5.18, 4.29 Hz, 2H).

Example 105

N-({3-(2-Cyclopropylethyl)-6-hydroxy-2,4-dioxo-1-[4-(2-thienyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

105a)1-(2-Cyclopropylethyl)-3-[4-(2-thienyl)phenyl]-2,4,6(1H,3H,5H)-pyrimidinetrione.Cyclopropylethylamine hydrochloride (608 mg, 4.96 mmoles) in chloroform(50 mL) was treated with diisopropylethylamine (2.1 mL, 12.0 mmoles)followed by 2-(4-isocyanatophenyl) thiophene (1.0 g, 4.96 mmoles). Themixture was stirred for 2 hours, malonyl dichloride (583 uL, 6.0 mmoles)was added and the mixture heated at 63° C. for 2 hours. The mixture waswashed with 1 molar hydrochloric acid and purified by flashchromatography (0-4.0% methanol in dichloromethane) to give the titlecompound (630 mg, 36%) 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.75 (d, J=8.59Hz, 2H), 7.61 (dd, J=5.05, 1.26 Hz, 1H), 7.57 (dd, J=3.54, 1.01 Hz, 1H),7.27 (d, J=8.59 Hz, 2H), 7.18 (dd, J=5.18, 3.66 Hz, 1H), 3.89 (s, 2H),3.84 (t, 2H), 1.44 (q, 2H), 0.63-0.76 (m, 1H), 0.37-0.46 (m, 2H), 0.05(q, J=4.80 Hz, 2H)

105b)N-({3-(2-Cyclopropylethyl)-1-[4-(2-thienyl)phenyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine.A mixture of1-(2-cyclopropylethyl)-3-[4-(2-thienyl)phenyl]-2,4,6(1H,3H,5H)-pyrimidinetrione(630 mg, 1.78 mmoles) and diisopropylethylamine (616 uL, 2.13 mmoles) indichloromethane (50 mL) was treated with ethyl isocyanatoacetate (239uL, 2.13 mmoles) and stirred overnight. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated. The residue wasdissolved in ethanol (5 mL) and treated with 6 molar sodium hydroxide(2.0 mL). The mixture was stirred for 2 hour, acidified and extractedwith ethyl acetate (×2), dried and evaporated. Flash chromatography(dichloromethane to 3.5% methanol-0.1% acetic acid) gave the titlecompound which was recrystallized from dichloromethane (300 mg, 37%). 1HNMR (400 MHz, DMSO-d₆) δ ppm 13.11 (s, 1H), 10.07 (s, 1H), 7.75 (ddd,J=8.72, 2.53, 2.15 Hz, 2H), 7.60 (ddd, J=9.79, 4.36, 1.01 Hz, 2H), 7.36(d, J=6.82 Hz, 2H), 7.18 (dd, J=5.05, 3.54 Hz, 1H), 4.14 (d, J=5.81 Hz,2H), 3.90-3.99 (m, 2H), 1.50 (q, J=7.07 Hz, 2H), 0.65-0.75 (m, 1H), 0.42(ddd, J=7.96, 5.68, 4.04 Hz, 2H), 0.03 (td, J=5.18, 4.29 Hz, 2H)

Example 106

N-{[1,3-Bis(1-ethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

106a) N,N′-Bis(1-ethylpropyl)urea. A mixture of carbonyldiimidazole (3.0g, 18.5 mmoles) and 3-aminopentane (4.66 mL, 40 mmoles) indimethylformamide (25 mL) was heated at 70° C. for 3 hours. The mixturewas cooled and partitioned between ethyl acetate and 1 molarhydrochloric acid. The aqueous was extracted with ethyl acetate and thecombined extracts washed with 1 molar hydrochloric acid, dried andevaporated to a solid (3.6 g, 97%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 5.37(s, 2H), 1.55 (q, J=7.33 Hz, 4H), 1.13 (s, 12H), 0.76 (t, J=7.45 Hz,6H).

106b) 1,3-Bis(1-ethylpropyl)-2,4,6(1H,3H,5H)-pyrimidinetrione.N,N′-bis(1-ethylpropyl)urea (1.03 g, 5.15 mmoles) in chloroform (60 mL)was treated with malonyl dichloride (600 uL, 6.2 mmoles) and heated at70° C. for 3 hours. The mixture was washed with 1 molar hydrochloricacid (×2), dried and evaporated. Flash chromatography (hexane-50% ethylacetate in hexane) gave the title compound (540 mg, 39%). 1H NMR (400MHz, CHLOROFORM-d) δ ppm 4.45-4.76 (m, 2H), 3.66 (s, 2H), 1.91-2.14 (m,4H), 1.55-1.87 (m, 4H), 0.85 (t, J=7.45 Hz, 12H)

106c)N-{[1,3-Bis(1-ethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of 1,3-bis(1-ethylpropyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(540 mg, 2.0 mmoles) and diisopropylethylamine (690 uL, 4.0 mmoles) indichloromethane (50 mL) was treated with ethyl isocyanatoacetate (270uL, 2.4 mmoles) and stirred overnight. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated. The residue wasdissolved in ethanol (6 mL) and treated with 6 molar sodium hydroxide(4.0 mL). The mixture was stirred for 72 hour, acidified and extractedwith ethyl acetate (×2), dried and evaporated. The residue was stored at−10° C. overnight, crystallized. The solid was slurried in hexane,collected, washed with hexane to give the title compound (300 mg, 40%).1H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (br. s, 1H), 10.20 (br s, 1H),4.65 (br. s, 2H), 4.13 (d, J=5.81 Hz, 2H), 2.02 (br. s, 4H), 1.69 (br.s, 4H), 0.77 (t, J=7.33 Hz, 12H)

Example 107

N-[(6-Hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

Barbituric acid (512 mg, 4 mmol) was dissolved in a mixture ofdichloromethane (3 mL) and DMF (5 mL). N,N-Diisopropylethylamine (2 mL)was added followed by ethyl isocyanatoacetate (645 mg, 5 mmol) and thesolution was stirred overnight. After evaporation of all volatiles, theresidue was re-dissolved in a mixture of ethanol (5 mL) and 1M aqueousNaOH (5 mL). After stirring at room temperature for one hour, thissolution was neutralized by addition of 1M aqueous HCl. The resultingsolid was collected, washed with water, and dried under vacuum overnightto give the title compound (202 mg, 22%). LC/MS m/z 230 (M+H⁺).

Example 108

N-[(1-Cyclohexyl-6-hydroxy-2,4-dioxo-3-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles)and 4-trifluoromethylbenzyl bromide (478 uL, 2.0 mmoles) indimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours.The mixture was poured into 1 molar hydrochloric acid and extracted withethyl acetate (×2). The combined organic solutions were washed with 1molar hydrochloric acid and evaporated. The residue was purified byflash chromatography (10-50% ethyl acetate in hexane), the requiredfractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodiumhydroxide solution (3.0 mL) added. The mixture was stirred overnight,acidified and extracted with ethyl acetate (×2), the combined extractswashed with 1 molar hydrochloric acid, dried and evaporated.Recrystallization from ethanol-water gave the title compound (176 mg,37.5%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (br. s., 1H), 10.13 (br.s., 1H), 7.69 (d, J=8.08 Hz, 2H), 7.51 (d, J=8.08 Hz, 2H), 5.07 (s, 2H),4.64 (t, J=12.13 Hz, 1H), 4.13 (d, J=5.81 Hz, 2H), 2.13-2.32 (m, 2H),1.78 (d, J=12.63 Hz, 2H), 1.50-1.72 (m, 3H), 1.28 (q, 2H), 1.11 (q,J=13.22 Hz, 1H).

Example 109

N-[(1,3-Dibutyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

109a) 1,3-Dibutyl-2,4,6(1H,3H,5H)-pyrimidinetrione. 1-Butylisocyanate(2.25 ml, 20 mmoles) and butylamine (1.98 mL, 20 mmoles) were stirredtogether in dichloromethane (100 mL) for 2 hours. Malonyl dichloride(2.14 mL, 22 mmoles) was added and the mixture was heated under gentlereflux for 2 hours. The mixture was washed with 1 molar hydrochloricacid (×2), dried and evaporated. Flash chromatography (hexane-25% ethylacetate-hexane) gave the title compound (1.32 g, 27%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 3.65-3.77 (m, 6H), 1.48 (tt, 4H), 1.28 (tq, J=7.49, 7.33Hz, 4H), 0.89 (t, J=7.33 Hz, 6H)

109b)N-[(1,3-Dibutyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.A mixture of 1,3-dibutyl-2,4,6(1H,3H,5H)-pyrimidinetrione (1.3 g mg, 5.5mmoles) and diisopropylethylamine (1.9 mL, 11.0 mmoles) indichloromethane (20 mL) was treated with ethyl isocyanatoacetate (673uL, 6.0 mmoles) and stirred for 24 hours. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated. The residue wastaken up in ethanol (5 mL) and treated with 6 molar sodium hydroxide (3mL) and stirred for 2 hours. The mixture was acidified with 1 molarhydrochloric acid and stirred for 30 minutes to give a solid which wasrecrystallized from acetic acid-water to afford the title compound (1.2g, 64%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (br. s., 1H), 10.11 (t,J=6.19 Hz, 1H), 4.13 (d, J=5.81 Hz, 2H), 3.81 (t, 4H), 1.43-1.63 (m,4H), 1.14-1.41 (m, 4H), 0.89 (t, J=7.33 Hz, 6H).

Example 110

N-{[1,3-Bis(2-cyclopropylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

110a) N,N′-Bis(2-cyclopropylethyl)urea. A mixture ofcyclopropylethylamine hydrochloride (5.15 g, 42.35 mmoles), sodiumcarbonate (4.56 g, 43 mmoles) and carbonyldiimidazole (2.99 g, 18.4mmoles) in dimethylformamide (30 mL) was sealed in a pressure flask andheated at 100° C. for 2 hours. The mixture was acidified with 1 molarhydrochloric acid and extracted into ethyl acetate (×2). The combinedextracts were washed with 1 molar hydrochloric acid, dried andevaporated to give the title compound (3.28 g, 79%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 5.77 (br. s., 2H), 3.03 (t, J=6.95 Hz, 4H), 1.25 (q,J=7.07 Hz, 4H), 0.50-0.76 (m, 2H), 0.26-0.48 (m, 4H), −0.17-0.16 (m, 4H)

110b) 1,3-Bis(2-cyclopropylethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione.Malonyl dichloride (2.02 mL, 20.8 mmoles) was added to a solution ofN,N′-bis(2-cyclopropylethyl)urea (3.26 g, 16.6 mmoles) indichloromethane (200 mL) and the mixture was heated under gentle refluxfor 2 hours. The mixture was washed with 1 molar hydrochloric acid,evaporated and purified by flash chromatography (hexane-25% ethylacetate-hexane) gave the title compound (1.05 g, 24%). 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 3.94 (t, 4H), 3.61 (s, 2H), 1.46 (q, 4H), 0.55-0.75(m, 2H), 0.33-0.49 (m, 4H), −0.04-0.08 (m, 4H)

110c)N-{[1,3-Bis(2-cyclopropylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of1,3-bis(2-cyclopropylethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (1.05 g,3.97 mmoles) and diisopropylethylamine (1.51 mL, 8.7 mmoles) indichloromethane (50 mL) was treated with ethyl isocyanatoacetate (980uL, 8.7 mmoles) and stirred overnight. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated. The residue wastaken up in ethanol (6 mL) and treated with 6 molar sodium hydroxide (4mL) and stirred for 2 hours. The mixture was acidified with 1 molarhydrochloric acid and stirred for 30 minutes to give a solid which wasrecrystallized from acetic acid-water to afford the title compound (1.1g, 76%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.09 (br. s, 1H), 10.10 (t,J=5.81 Hz, 1H), 4.13 (d, J=5.81 Hz, 2H), 3.86-3.95 (m, 4H), 1.45 (q,J=7.07 Hz, 4H), 0.62-0.72 (m, J=15.13, 12.28, 7.33, 4.93 Hz, 2H), 0.38(ddd, J=7.96, 5.68, 4.04 Hz, 4H), −0.00 (q, J=4.80 Hz, 4H)

Example 111

N-{[6-Hydroxy-1,3-bis(2-methylpropyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

111a) N,N′-Bis(2-methylpropyl)urea. A mixture of isobutylamine (3.98 mL,40 mmoles) and carbonyldiimidazole (3.0 g, 18.5 mmoles) indimethylformamide (6 mL) was sealed in a pressure flask and heated at75° C. for 2 hours. The mixture was acidified with 1 molar hydrochloricacid and extracted into ethyl acetate (×2). The combined extracts werewashed with 1 molar hydrochloric acid, dried and evaporated to give thetitle compound (3.2 g, 93%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 5.79 (br.s., 2H), 2.81 (d, J=6.82 Hz, 4H), 1.59 (dq, J=13.39, 6.69 Hz, 2H), 0.82(d, J=6.82 Hz, 12H)

111b) 1,3-Bis(2-methylpropyl)-2,4,6(1H,3H,5H)-pyrimidinetrione. Malonyldichloride (2.2 mL, 22.3 mmoles) was added to a solution ofN,N′-bis(2-methylpropyl)urea (3.2 g, 18.6 mmoles) in dichloromethane(175 mL) and the mixture was heated under gentle reflux for 2 hours. Themixture was washed with 1 molar hydrochloric acid, evaporated andpurified by flash chromatography (hexane-25% ethyl acetate-hexane) gavethe title compound (3.38 g, 76%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm3.75 (d, J=7.33 Hz, 4H), 3.70 (s, 2H), 2.07 (dq, J=13.89, 7.07 Hz, 2H),0.92 (d, J=6.82 Hz, 12H)

111c)N-{[6-Hydroxy-1,3-bis(2-methylpropyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of 1,3-bis(2-methylpropyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(3.3 g, 13.73 mmoles) and diisopropylethylamine (5.2 mL, 30 mmoles) indichloromethane (100 mL) was treated with ethyl isocyanatoacetate (3.36mL, 30 mmoles) and stirred overnight. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated to a solid which wasslurried in hexane and collected. The solid was taken up in ethanol (10mL) and treated with 6 molar sodium hydroxide (6 mL) and stirred for 2hours. The mixture was acidified with 6 molar hydrochloric acid anddiluted with 6 molar hydrochloric acid stirred for 30 minutes to give asolid which was recrystallized from acetic acid-water to afford thetitle compound (3.15 g, 67%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.11 (br.s, 1H), 10.13 (t, J=5.81 Hz, 1H), 4.13 (d, J=5.81 Hz, 2H), 3.67 (d,J=7.33 Hz, 4H), 2.02 (dq, J=13.80, 6.92 Hz, 2H), 0.85 (d, J=6.82 Hz,12H)

Example 112

N-({3-(2-Cyclopropylethyl)-6-hydroxy-1-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

112a)1-(2-Cyclopropylethyl)-3-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,4,6(1H,3H,5H)-pyrimidinetrione.Cyclopropylethylamine hydrochloride (588 mg, 4.84 mmoles) in chloroform(50 mL) was treated with diisopropylethylamine (2.1 mL, 12.0 mmoles)followed by 3-(3-isocyanatophenyl)-5-methyl-1,2,4-oxadiazole (973 mg,4.84 mmoles). The mixture was stirred for 2 hours, malonyl dichloride(583 uL, 6.0 mmoles) was added and the mixture heated at 63° C. for 2hours. The mixture was washed with 1 molar hydrochloric acid andpurified by flash chromatography (0-4.0% methanol in dichloromethane) togive the title compound (425 mg, 25%) 1H NMR (400 MHz, CHLOROFORM-d) δppm 8.19 (ddd, J=7.96, 1.39, 1.26 Hz, 1H), 7.95 (t, J=1.77 Hz, 1H), 7.64(t, J=8.08 Hz, 1H), 7.36 (ddd, J=7.96, 2.15, 1.01 Hz, 1H), 4.03-4.09 (m,2H), 3.89 (s, 2H), 2.68 (s, 3H), 1.54-1.57 (m, 1H), 0.67-0.77 (m, 1H),0.46-0.52 (m, 2H), 0.10 (td, J=5.24, 4.42 Hz, 2H)

112b)N-({3-(2-Cyclopropylethyl)-6-hydroxy-1-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine.A mixture of1-(2-cyclopropylethyl)-3-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,4,6(1H,3H,5H)-pyrimidinetrione(418 mg, 1.18 mmoles) and diisopropylethylamine (408 uL, 2.36 mmoles) indichloromethane (50 mL) was treated with ethyl isocyanatoacetate (160uL, 1.41 mmoles) and stirred overnight. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated. The residue wasdissolved in ethanol (5 mL) and treated with 6 molar sodium hydroxide(2.0 mL). The mixture was stirred for 2 hour, acidified and extractedwith ethyl acetate (×2), dried and evaporated. Flash chromatography(dichloromethane to 3.5% methanol-0.1% acetic acid) gave the titlecompound which was recrystallized from acetic acid-water (290 mg, 54%).1H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (br. s, 1H), 10.06 (br. s, 1H),8.05 (d, J=7.83 Hz, 1H), 7.98 (s, 1H), 7.67 (t, J=7.83 Hz, 1H). 7.55 (d,J=7.33 Hz, 1H), 4.14 (d, J=5.81 Hz, 2H), 3.88-3.98 (m, 2H), 2.68 (s,3H), 1.50 (q, J=7.16 Hz, 2H), 0.66-0.76 (m, 1H), 0.42 (ddd, J=7.83,5.68, 4.17 Hz, 2H), −0.01-0.08 (m, 2H).

Example 113

N-({3-(2-Cyclopropylethyl)-6-hydroxy-1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

113a)1-(2-Cyclopropylethyl)-3-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]-2,4,6(1H,3H,5H)-pyrimidinetrione.Cyclopropylethylamine hydrochloride (620 mg, 5.1 mmoles) in chloroform(50 mL) was treated with diisopropylethylamine (2.1 mL, 12.0 mmoles)followed by 4-(4-isocyanatophenyl)-2-methyl-1,3-thiazole (1.1 g, 5.1mmoles). The mixture was stirred for 2 hours, malonyl dichloride (583uL, 6.0 mmoles) was added and the mixture heated at 63° C. for 2 hours.The mixture was washed with 1 molar hydrochloric acid and purified byflash chromatography (0-7.0% methanol in dichloromethane) to give thetitle compound (620 mg, 33%) 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.03(d, J=8.59 Hz, 2H), 7.39 (s, 1H), 7.26 (d, J=8.84 Hz, 2H), 4.01-4.10 (m,2H), 3.88 (s, 2H), 2.81 (s, 3H), 1.58 (q, 2H), 0.67-0.78 (m, 1H),0.44-0.50 (m, 2H), 0.06-0.13 (m, 2H)

113b)N-({3-(2-Cyclopropylethyl)-6-hydroxy-1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine.A mixture of1-(2-cyclopropylethyl)-3-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]-2,4,6(1H,3H,5H)-pyrimidinetrione(618 mg, 1.67 mmoles) and and diisopropylethylamine (578 uL, 3.34mmoles) in dichloromethane (50 mL) was treated with ethylisocyanatoacetate (224 uL, 2.0 mmoles) and stirred overnight. Themixture was washed with 1 molar hydrochloric acid (×2), dried andevaporated. The residue was dissolved in ethanol (5 mL) and treated with6 molar sodium hydroxide (2.0 mL). The mixture was stirred for 2 hour,acidified and extracted with ethyl acetate (×2), dried and evaporated.Flash chromatography (dichloromethane to 3.5% methanol-0.1% acetic acid)gave the title compound which was obtained as a solid from diethylether. (210 mg, 27%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.11 (br. s, 1H),10.08 (br. s, 1H), 7.97-8.05 (m, 3H), 7.37 (d, J=6.82 Hz, 2H), 4.14 (d,J=5.56 Hz, 2H), 3.88-3.98 (m, 2H), 2.74 (s, 3H), 1.50 (q, J=7.07 Hz,2H), 0.65-0.75 (m, 1H), 0.37-0.46 (m, 2H), 0.03 (q, J=4.72 Hz, 2H).

Example 114

N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(4-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

114a) Phenylmethyl4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-piperidinecarboxylate. Amixture of benzyl 4-hydroxy-1-piperidine carboxylate (2.0 g, 8.5mmoles), phthalimide (2.5 g, 17 mmoles), triphenylphosphine (4.46 g, 17mmoles) and diisopropyl azodicarboxylate (3.345 mL, 17 mmoles) werestirred together in tetrahydrofuran (60 mL) for 5 hours. The mixture wasevaporated onto silica gel and chromatographed (hexane to 60% ethylacetate-hexane). The fractions afforded crystalline product on standing(1.5 g, 48%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.76-7.94 (m, 5H),7.37-7.41 (m, 3H), 7.30-7.37 (m, 1H), 4.71-4.83 (m, 1H), 4.18-4.29 (m,1H), 4.14 (d, J=13.64 Hz, 2H), 2.16 (dd, 2H), 1.73 (d, J=10.36 Hz, 2H),1.18 (d, J=6.32 Hz, 2H)

114b) Phenylmethyl 4-amino-1-piperidinecarboxylate. A mixture ofphenylmethyl4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-piperidinecarboxylate (1.5g, 4.11 mmoles) and 25% hydrazine hydrate (10.0 mL) in ethanol (20 mL)was heated under reflux for 30 minutes. The mixture was evaporated,re-diluted with ethanol and re-evaporated to a solid. The solid wasslurried in diethyl ether, collected, washed with diethyl ether and thefiltrate evaporated to give the title compound as an oil (quant.) 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.25-7.45 (m, 5H), 5.14 (s, 2H), 4.89-5.07(m, 1H), 3.18-3.42 (m, 2H), 2.76-2.95 (m, 2H), 1.74-1.94 (m, 2H),1.51-1.68 (m, 2H), 1.28 (d, J=6.06 Hz, 2H).

114c) Phenylmethyl4-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)-1-piperidinecarboxylate.A mixture of phenylmethyl 4-amino-1-piperidinecarboxylate (700 mg, 2.98mmoles) and cyclohexyl isocyanate (457 uL, 3.6 mmoles) was stirred inchloroform (60 mL) for 2 hours. Malonyl dichloride (350 uL, 3.6 mmoles)was added and the mixture was stirred at 50° C. for 2 hours. The mixturewas washed with 1 molar hydrochloric acid (×2) and evaporated ontosilica gel. Flash chromatography (dichloromethane to 30% methanol indichloromethane) gave the title compound (350 mg, 80%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 7.24-7.47 (m, 5H), 5.10 (s, 2H), 4.61-4.78 (m, 1H),4.35-4.52 (m, 1H), 4.09 (d, J=10.86 Hz, 2H), 3.70 (s, 2H), 2.85 (d,J=26.02 Hz, 2H), 2.20-2.33 (m, 2H), 2.14 (dd, 1H), 1.78 (d, 2H), 1.58(d, J=11.12 Hz, 4H), 1.00-1.34 (m, 5H).

114d)N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(4-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of phenylmethyl4-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)-1-piperidinecarboxylate(530 mg, 1.24 mmoles) and diisopropylethylamine (536 uL, 3.1 mmoles) inchloroform (50 mL) was treated with ethyl isocyanatoacetate (225 uL, 2.0mmoles) and stirred overnight. The mixture was washed with 1 molarhydrochloric acid (×2), dried and evaporated. The residue was dissolvedin isopropanol (30 mL), the solution flushed with argon and 10%palladium on charcoal catalyst (100 mg) added. The mixture was shaken ina hydrogen atmosphere at 50 psi for 2 hours. The mixture was filtered,evaporated and treated with 1 molar sodium hydroxide solution overnight.Acidified and extracted into ethyl acetate. Preparative HPLC (10 to 80%acetonitrile-water-0.1% TFA) gave the title compound (120 mg, 24%). 1HNMR (400 MHz, DMSO-d₆) δ ppm 13.17 (s, 1H), 10.18 (s, 1H), 8.74 (d,J=11.12 Hz, 1H), 8.32-8.40 (m, 1H), 8.29 (s, 1H), 4.95 (t, J=12.63 Hz,1H), 4.63 (t, J=12.63 Hz, 1H), 4.15 (d, J=5.81 Hz, 2H), 3.36 (d, J=12.13Hz, 2H), 3.02 (q, J=12.55 Hz, 2H), 2.61-2.73 (m, 2H), 2.20-2.31 (m, 2H),1.79 (d, J=12.38 Hz, 4H), 1.62 (s, 3H), 1.22-1.34 (m, 2H), 1.10 (d,J=16.42 Hz, 1H).

Example 115

N-({3-(2-Cyclopropylethyl)-1-[4-(2-furanyl)phenyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

115a)1-(2-Cyclopropylethyl)-3-[4-(2-furanyl)phenyl]-2,4,6(1H,3H,5H)-pyrimidinetrione.Cyclopropylethylamine hydrochloride (693 mg, 5.67 mmoles) in chloroform(50 mL) was treated with diisopropylethylamine (1.04 mL, 6.0 mmoles)followed by 2-(4-isocyanatophenyl) furan (1.05 g, 5.67 mmoles). Themixture was stirred for 2 hours, malonyl dichloride (665 uL, 6.84mmoles) was added and the mixture heated at 63° C. for 2 hours. Themixture was washed with 1 molar hydrochloric acid and purified by flashchromatography (0-3.5% methanol in dichloromethane) to give the titlecompound (330 mg, 17%) 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.75 (d, J=8.59Hz, 2H), 7.59-7.63 (m, 1H), 7.55-7.59 (m, 1H), 7.27 (d, J=8.59 Hz, 2H),7.18 (dd, J=5.05, 3.54 Hz, 1H), 3.88 (s, 2H), 3.84 (t, 2H), 1.44 (q,J=7.33 Hz, 2H), 0.63-0.76 (m, 1H), 0.36-0.44 (m, 2H), 0.01-0.07 (m, 2H)

115b)N-({3-(2-Cyclopropylethyl)-1-[4-(2-furanyl)phenyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine.A mixture1-(2-cyclopropylethyl)-3-[4-(2-furanyl)phenyl]-2,4,6(1H,3H,5H)-pyrimidinetrione(330 mg, 0.976 mmoles) and diisopropylethylamine (337 uL, 1.95 mmoles)in dichloromethane (80 mL) was treated with ethyl isocyanatoacetate (131uL, 1.17 mmoles) and stirred overnight. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated. The residue wasdissolved in ethanol (5 mL) and treated with 6 molar sodium hydroxide(2.0 mL). The mixture was stirred for 2 hour, acidified and extractedwith ethyl acetate (×2), dried and evaporated. Flash chromatography(dichloromethane to 3.5% methanol-0.1% acetic acid); material stillimpure, re-chromatographed (hexane-ethyl acetate) gave the titlecompound (30 mg, 7%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (s, 1H),10.08 (br. s., 1H), 7.80 (s, 2H), 7.78 (s, 1H), 7.36 (d, J=7.33 Hz, 2H),7.04 (d, J=3.28 Hz, 1H), 6.64 (dd, J=3.28, 1.77 Hz, 1H), 4.14 (d, J=5.81Hz, 2H), 3.94 (t, 2H), 1.50 (q, J=6.65 Hz, 2H), 0.63-0.77 (m, 1H),0.36-0.46 (m, 2H), −0.01-0.07 (m, 2H).

Example 116

N-{[1,3-Bis(1,1-dimethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

116a) N,N′-Bis(1,1-dimethylpropyl)urea. A mixture of carbonyldiimidazole(3.0 g, 18.5 mmoles) and t-amylamine (4.7 mL, 40 mmoles) indimethylformamide (25 mL) was heated at 70° C. for 3 hours. The mixturewas cooled and partitioned between ethyl acetate and 1 molarhydrochloric acid. The aqueous was extracted with ethyl acetate and thecombined extracts washed with 1 molar hydrochloric acid, dried andevaporated to a solid (2.9 g, 78%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 5.37(s, 2H), 1.55 (q, J=7.33 Hz, 4H), 1.13 (s, 12H), 0.76 (t, J=7.45 Hz,6H).

116b) 1,3-Bis(1,1-dimethylpropyl)-2,4,6(1H,3H,5H)-pyrimidinetrione.N,N′-bis(1,1-dimethylpropyl)urea (1.6 g, 8.0 mmoles) in chloroform (60mL) was treated with malonyl dichloride (935 uL, 9.6 mmoles) and heatedat 70° C. for 3 hours. The mixture was washed with 1 molar hydrochloricacid (×2), dried and evaporated. Flash chromatography (hexane-50% ethylacetate in hexane) gave the title compound (960 mg, 44%). 1H NMR (400MHz, CHLOROFORM-d) δ ppm 3.49 (s, 2H), 2.04 (q, J=7.41 Hz, 4H), 1.55 (s,12H), 0.85 (t, J=7.45 Hz, 6H).

116c)N-{[1,3-Bis(1,1-dimethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of1,3-bis(1,1-dimethylpropyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (960 mg,3.5 mmoles) and diisopropylethylamine (1.21 mL, 7.0 mmoles) indichloromethane (50 mL) was treated with ethyl isocyanatoacetate (482uL, 4.3 mmoles) and stirred overnight. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated. The residue wasdissolved in ethanol (10 mL) and treated with 6 molar sodium hydroxide(5.0 mL). The mixture was stirred for 72 hour, acidified and extractedwith ethyl acetate (×2), dried and evaporated. The residue was stored at−10° C. overnight, crystallized. The solid was slurried in hexane,collected, washed with hexane to give the title compound (600 mg, 46%).1H NMR (400 MHz, DMSO-d₆) δ ppm 12.71 (br. s, 1H), 10.12 (t, J=6.06 Hz,1H), 4.08 (d, J=5.81 Hz, 2H), 2.00-2.10 (m, 4H), 1.54 (s, 12H), 0.79 (m,6H).

Example 117

N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

117a) Phenylmethyl3-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)-1-piperidinecarboxylate.A mixture of benzyl 3-aminopiperidine-1-carboxylate hydrochloride (1.51g, 5.57 mmoles), diisopropylethylamine (965 uL, 5.57 mmoles) andcyclohexylisocyanate (708 uL, 5.57 mmoles) were stirred together indichloromethane (60 mL) overnight. The mixture was washed with 1 molarhydrochloric acid (×2) and the solution dried. Malonyl dichloride (650uL, 6.68 mmoles) was added and the mixture was heated under gentlereflux for 4 hours. The mixture was washed with 1 molar hydrochloricacid (×2) and the solution dried and evaporated. The title compound wasobtained as a solid from diethyl ether (1.0 g, 42%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 7.24-7.47 (m, 5H), 5.09 (s, 2H), 4.35-4.58 (m, 2H), 3.98(d, 2H), 3.68 (d, J=4.29 Hz, 2H), 3.35-3.60 (m, 1H), 2.32 (q, 1H),2.07-2.21 (m, 2H), 1.66-1.87 (m, 5H), 1.53-1.65 (m, 3H), 1.36-1.50 (m,1H), 1.26 (q, J=13.05 Hz, 2H), 1.03-1.15 (m, 1H)

117b) Phenylmethyl3-[3-cyclohexyl-5-({[2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-1-piperidinecarboxylate.A mixture of phenylmethyl3-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)-1-piperidinecarboxylate(1.0 g, 3.5 mmole) and diisopropylethylamine (1.2 mL, 7.0 mmoles) indichloromethane (60 mL) was treated with ethyl isocyanatoacetate (450uL, 4.0 mmoles) and stirred overnight. The mixture was washed with 1molar hydrochloric acid (×2), dried and evaporated to a glassy solid(1.3 g, 67%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 10.17 (br. s., 1H),7.15-7.51 (m, 5H), 4.93-5.26 (m, 2H), 4.50-4.79 (m, 2H), 4.17-4.27 (m,2H), 4.08-4.17 (m, 2H), 3.93-4.07 (m, 2H), 3.51-3.73 (m, 1H), 2.58-2.85(m, 1H), 2.33-2.48 (m, 1H), 2.11-2.34 (m, 2H), 1.68-1.86 (m, 4H), 1.62(d, J=11.62 Hz, 3H), 1.35-1.53 (m, 1H), 1.24-1.34 (m, 2H), 1.16-1.26 (m,4H), 1.02-1.18 (m, 1H)

117c)N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinehydrobromide. Phenylmethyl3-[3-cyclohexyl-5-({[2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-1-piperidinecarboxylate(1.2 g, 2.15 mmoles) was stirred in a mixture of acetic acid (30 mL) and48% hydrobromic acid (5.0 mL) for 40 hours—reaction incomplete. Themixture was then heated at 60° C. for 2 hours, diluted with water andextracted with ethyl acetate (×5). The combined extracts were dried andevaporated, and recrystallized from diethyl ether-hexane to give thetitle compound (160 mg, 20%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 12.84 (br.s., 1H), 10.11 (s, 1H), 8.86 (s, 1H), 5.12 (s, 1H), 4.63 (t, J=12.00 Hz,1H), 4.09 (s, 2H), 3.66 (t, J=11.37 Hz, 1H), 3.28 (d, J=10.61 Hz, 2H),2.77 (t, J=11.12 Hz, 1H), 2.36 (dd, J=12.38, 3.54 Hz, 1H), 2.22-2.32 (m,2H), 1.89 (d, J=12.63 Hz, 1H), 1.69-1.81 (m, 4H), 1.55-1.67 (m, 4H),1.27 (q, J=12.88 Hz, 2H), 1.11 (q, J=12.97 Hz, 1H)

Example 118

N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(1-{[(phenylmethyl)oxy]carbonyl}-3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

Phenylmethyl3-[3-cyclohexyl-5-({[2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-1-piperidinecarboxylate(100 mg, 0.18 mmoles) was dissolved in ethanol (3.0 mL) and treated with6 molar sodium hydroxide (1.5 mL). The mixture was stirred for 2 hours,acidified and extracted with ethyl acetate (×2). The combined extractswere washed with 1 molar hydrochloric acid, dried and evaporated to afoam (80 mg, 84%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.11 (s, 1H), 10.17(s, 1H), 7.30-7.40 (m, 5H), 5.10 (s, 2H), 4.57-4.69 (m, 2H), 4.13 (d,J=5.81 Hz, 2H), 3.95-4.05 (m, 2H), 3.64 (s, 1H), 3.37 (s, 1H), 2.73 (s,1H), 2.36-2.48 (m, 1H), 2.25 (q, J=11.62 Hz, 2H), 1.70-1.82 (m, 4H),1.62 (d, J=11.37 Hz, 3H), 1.38-1.50 (m, 1H), 1.21-1.33 (m, 2H),1.06-1.18 (m, 1H)

Example 119

N-{[1-(1-Acetyl-3-piperidinyl)-3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

A solution ofN-{[3-cyclohexyl-6-hydroxy-2,4-dioxo-1-(3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine(500 mg, 1.26 mmoles) in acetic acid (5.0 mL) and acetic anhydride (5.0mL) was heated at 130° C. for 2 hours. The mixture was cooled, dilutedwith ethyl acetate and washed with 1 molar hydrochloric acid (×3), driedand evaporated. Flash chromatography (dichloromethane to 4%methanol-0.1% acetic acid in dichloromethane) and recrystallization fromethanol-water gave the title compound (170 mg, 31%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.10 (br. s., 1H), 10.17 (s, 1H), 4.46-4.73 (m, 2H),4.25-4.46 (m, 1H), 4.13 (d, J=5.56 Hz, 2H), 3.67-3.92 (m, J=4.55 Hz,1H), 3.24-3.43 (m, 1H), 2.94 (t, J=12.63 Hz, 1H), 2.34-2.48 (m, 1H),2.25 (m, 2H), 1.97, 2.02 (2×s, 3H), 1.69-1.87 (m, 4H), 1.62 (m, 3H),1.41-1.57 (m, 1H), 1.19-1.37 (m, 2H), 0.97-1.18 (m, 1H)

Example 120

N-[(1-Cyclohexyl-3-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles)and 4-fluoro-2-trifluoromethylbenzyl bromide (455 mg, 1.77 mmoles) indimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours.The mixture was poured into 1 molar hydrochloric acid and extracted withethyl acetate (×2). The combined organic solutions were washed with 1molar hydrochloric acid and evaporated. The residue was purified byflash chromatography (10-50% ethyl acetate in hexane), the requiredfractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodiumhydroxide solution (3.0 mL) added. The mixture was stirred overnight,acidified and extracted with ethyl acetate (×2), the combined extractswashed with 1 molar hydrochloric acid, dried and evaporated.Recrystallization from hexane gave the title compound (184 mg, 38%). 1HNMR (400 MHz, DMSO-d₆) δ ppm 13.10 (br. s., 1H), 10.11 (br. s., 1H),7.67 (dd, J=9.09, 2.78 Hz, 1H), 7.45 (ddd, J=8.40, 2.65 Hz, 1H), 7.29(dd, J=8.59, 5.31 Hz, 1H), 5.13 (s, 2H), 4.64 (t, J=12.00 Hz, 1H), 4.13(d, J=5.81 Hz, 2H), 2.24 (q, 2H), 1.78 (d, J=12.63 Hz, 2H), 1.53-1.73(m, 3H), 1.28 (q, J=12.72 Hz, 2H), 1.10 (q, J=12.63 Hz, 1H)

Example 121

N-({3-[(2-Bromophenyl)methyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles)and 2-bromobenzyl bromide (480 mg, 1.92 mmoles) in dimethylacetamide (6mL) was vigorously stirred at 100° C. for 3 hours. The mixture waspoured into 1 molar hydrochloric acid and extracted with ethyl acetate(×2). The combined organic solutions were washed with 1 molarhydrochloric acid and evaporated. The residue was purified by flashchromatography (10-50% ethyl acetate in hexane), the required fractionsevaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxidesolution (3.0 mL) added. The mixture was stirred overnight, acidifiedand extracted with ethyl acetate (×2), the combined extracts washed with1 molar hydrochloric acid, dried and evaporated. Recrystallization fromethanol-water gave the title compound (150 mg, 38%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.11 (br. s., 1H), 10.12 (br. s., 1H), 7.65 (dd, J=7.96,1.14 Hz, 1H), 7.32 (ddd, J=7.52, 1.14 Hz, 1H), 7.22 (ddd, J=7.64, 1.64Hz, 1H), 7.03 (dd, J=7.58, 1.26 Hz, 1H), 5.00 (s, 2H), 4.65 (t, J=12.13Hz, 1H), 4.13 (d, J=5.81 Hz, 2H), 2.25 (q, 2H), 1.79 (d, J=12.88 Hz,2H), 1.54-1.72 (m, 3H), 1.28 (q, J=13.14 Hz, 2H), 1.10 (q, J=12.38 Hz,1H)

Example 122

N-({1-Cyclohexyl-3-[(2,6-dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles)and 2,6-dichlorobenzyl bromide (440 mg, 2.0 mmoles) in dimethylacetamide(6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture waspoured into 1 molar hydrochloric acid and extracted with ethyl acetate(×2). The combined organic solutions were washed with 1 molarhydrochloric acid and evaporated. The residue was purified by flashchromatography (10-50% ethyl acetate in hexane), the required fractionsevaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxidesolution (3.0 mL) added. The mixture was stirred overnight, acidifiedand extracted with ethyl acetate (×2), the combined extracts washed with1 molar hydrochloric acid, dried and evaporated. Recrystallization fromethanol-water gave the title compound (150 mg, 32%). 1H NMR (400 MHz,DMSO-d₆) δ ppm 13.07 (br. s., 1H), 9.98 (br. s., 1H), 7.43 (dd, 2H),7.30 (dd, 1H), 5.26 (s, 2H), 4.60 (t, J=12.00 Hz, 1H), 2.14-2.31 (m,2H), 1.77 (d, J=12.88 Hz, 2H), 1.47-1.66 (m, 3H), 1.27 (q, 2H), 1.10 (q,1H)

Example 123

N-[(3-{[2-Bromo-5-(methyloxy)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles)and 2-bromo-5-methoxybenzyl bromide (560 mg, 2.0 mmoles) indimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours.The mixture was poured into 1 molar hydrochloric acid and extracted withethyl acetate (×2). The combined organic solutions were washed with 1molar hydrochloric acid and evaporated. The residue was purified byflash chromatography (10-50% ethyl acetate in hexane), the requiredfractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodiumhydroxide solution (3.0 mL) added. The mixture was stirred overnight,acidified and extracted with ethyl acetate (×2), the combined extractswashed with 1 molar hydrochloric acid, dried and evaporated.Recrystallization from acetic acid-water gave the title compound (150mg, 29%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.04 (br. s., 1H), 10.12 (br.s., 1H), 7.55 (d, J=8.84 Hz, 1H), 6.84 (dd, J=8.84, 3.03 Hz, 1H), 6.50(d, J=2.78 Hz, 1H), 4.94 (s, 2H), 4.65 (t, J=11.75 Hz, 1H), 4.13 (d,J=5.81 Hz, 2H), 3.69 (s, 3H), 2.25 (q, 2H), 1.79 (d, J=13.14 Hz, 2H),1.54-1.74 (m, 3H), 1.28 (q, J=12.72 Hz, 2H), 1.10 (q, J=12.88 Hz, 1H)

Example 124

N-[(3-{[2,4-Bis(trifluoromethyl)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles)and 2,4-bis(trifluoromethyl)benzyl bromide (375 uL, 2.0 mmoles) indimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours.The mixture was poured into 1 molar hydrochloric acid and extracted withethyl acetate (×2). The combined organic solutions were washed with 1molar hydrochloric acid and evaporated. The residue was purified byflash chromatography (10-50% ethyl acetate in hexane), the requiredfractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodiumhydroxide solution (3.0 mL) added. The mixture was stirred overnight,acidified and extracted with ethyl acetate (×2), the combined extractswashed with 1 molar hydrochloric acid, dried and evaporated.Recrystallization from acetic acid-water gave the title compound (180mg, 34%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.11 (br. s., 1H), 8.06 (s,1H), 7.98 (d, J=8.59 Hz, 1H), 7.53 (d, J=8.34 Hz, 1H), 5.23 (s, 2H),4.64 (t, J=12.00 Hz, 1H), 4.13 (d, J=5.56 Hz, 2H), 2.24 (q, 2H), 1.78(d, J=12.63 Hz, 2H), 1.52-1.73 (m, 3H), 1.28 (q, J=13.05 Hz, 2H), 1.10(q, 1H).

Example 125

N-({3-[(2-Bromo-5-fluorophenyl)methyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles)and 2-bromo-5-fluorobenzyl bromide (375 uL, 2.0 mmoles) indimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours.The mixture was poured into 1 molar hydrochloric acid and extracted withethyl acetate (×2). The combined organic solutions were washed with 1molar hydrochloric acid and evaporated. The residue was purified byflash chromatography (10-50% ethyl acetate in hexane), the requiredfractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodiumhydroxide solution (3.0 mL) added. The mixture was stirred overnight,acidified and extracted with ethyl acetate (×2), the combined extractswashed with 1 molar hydrochloric acid, dried and evaporated.Recrystallization from acetic acid-water gave the title compound (160mg, 31%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (br. s., 1H), 10.10 (br.s., 1H), 7.69 (dd, J=8.59, 5.31 Hz, 1H), 7.11 (ddd, J=8.53, 3.16 Hz,1H), 7.05 (dd, J=9.60, 2.78 Hz, 1H), 4.95 (s, 2H), 4.63 (t, J=12.38 Hz,1H), 4.13 (d, J=5.81 Hz, 2H), 2.24 (q, 2H), 1.79 (d, J=13.14 Hz, 2H),1.52-1.74 (m, J=27.54, 11.62 Hz, 3H), 1.28 (q, J=12.88 Hz, 2H), 1.10 (q,J=12.97 Hz, 1H).

Example 126

N-[(3-{[2-Bromo-4-(1,1-dimethylethyl)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (740 mg, 5.35 mmoles)and 2-bromo-1-(bromomethyl)-4-(1,1-dimethylethyl)benzene (612 mg, 2.0mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C.for 3 hours. The mixture was poured into 1 molar hydrochloric acid andextracted with ethyl acetate (×2). The combined organic solutions werewashed with 1 molar hydrochloric acid and evaporated. The residue waspurified by flash chromatography (10-50% ethyl acetate in hexane), therequired fractions evaporated, dissolved in ethanol (5 mL) and 1 molarsodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide (1.0 mL)added. The mixture was stirred overnight, acidified and extracted withethyl acetate (×2), the combined extracts washed with 1 molarhydrochloric acid, dried and evaporated. Preparative HPLC (50-90%acetonitrile-water-0.1% TFA) gave the title compound (40 mg, 7.5%). 1HNMR (400 MHz, DMSO-d₆) δ ppm 13.17 (br. s., 1H), 10.14 (br. s., 1H),7.59 (d, J=1.52 Hz, 1H), 7.33 (dd, J=8.08, 1.52 Hz, 1H), 6.92 (d, J=8.08Hz, 1H), 4.96 (s, 2H), 4.65 (t, J=11.75 Hz, 1H), 4.13 (d, J=5.56 Hz,2H), 2.25 (q, J=11.54 Hz, 2H), 1.79 (d, J=12.13 Hz, 2H), 1.53-1.73 (m,3H), 1.20-1.38 (m, 11H), 1.11 (q, 1H)

Example 127

N-({1-Cyclohexyl-6-hydroxy-3-[(2-methylphenyl)methyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine

A mixture of ethylN-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate(340 mg, 1.0 mmoles), pulv. potassium carbonate (740 mg, 5.35 mmoles)and 2-methylbenzene (268 uL, 2.0 mmoles) in dimethylformamide (5 mL) wasvigorously stirred at 100° C. for 3 hours. The mixture was poured into 1molar hydrochloric acid and extracted with ethyl acetate (×2). Thecombined organic solutions were washed with 1 molar hydrochloric acidand evaporated. The residue was purified by flash chromatography (10-50%ethyl acetate in hexane), the required fractions evaporated, dissolvedin ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added.The mixture was stirred overnight, acidified and extracted with ethylacetate (×2), the combined extracts washed with 1 molar hydrochloricacid, dried and evaporated. Preparative HPLC (20-90%acetonitrile-water-0.1% TFA) gave the title compound (12 mg, 3.0%). 1HNMR (400 MHz, DMSO-d₆) δ ppm 13.11 (br. s., 1H), 10.15 (br. s., 1H),7.00-7.29 (m, 3H), 6.89 (d, J=6.82 Hz, 1H), 4.96 (s, 2H), 4.65 (t,J=12.25 Hz, 1H), 4.13 (d, J=5.56 Hz, 2H), 2.35 (s, 3H), 2.26 (q, 2H),1.78 (d, J=12.13 Hz, 2H), 1.51-1.72 (m, 3H), 1.28 (q, 2H), 1.10 (q, 1H).

Example 128

N-{[1-Cyclohexyl-3-(1,1-dimethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

128a)1-Cyclohexyl-3-(1,1-dimethylpropyl)-2,4,6(1H,3H,5H)-pyrimidinetrione. Amixture of t-amylamine (1.18 mL, 10 mmoles) and cyclohexyl isocyanate(1.28 mL, 10 mmoles) in chloroform (50 mL) was stirred overnight.Malonyl dichloride (1.16 mL, 12 mmoles) was added and the mixture washeated at 50° C. for 3 hours. The mixture was evaporated and flashchromatographed (ethyl acetate 10-50% in hexane) to give the titlecompound (1.9 g, 68%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.54 (tt,J=12.25, 3.66 Hz, 1H), 3.56 (s, 2H), 2.23 (ddd, J=24.88, 12.51, 3.54 Hz,2H), 2.06 (q, J=7.58 Hz, 2H), 1.77-1.91 (m, 2H), 1.52-1.72 (m, 9H), 1.35(qt, J=13.09, 3.28, 3.16 Hz, 2H), 1.22 (qt, J=12.87, 12.66, 3.28 Hz,1H), 0.83 (t, J=7.45 Hz, 3H)

128b)N-{[1-Cyclohexyl-3-(1,1-dimethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of1-cyclohexyl-3-(1,1-dimethylpropyl)-2,4,6(1H,3H,5H)-pyrimidinetrione(1.9 g, 6.8 mmoles), diisopropylethylamine (2.35 mL, 13.6 mmoles) andethyl isocyanatoacetate (915 uL, 8.16 mmoles) in dichloromethane (60 mL)was stirred for 72 hours. The mixture was washed with 1 molarhydrochloric acid (×2) and evaporated. The residue was dissolved inethanol (10 mL), treated with 6 molar sodium hydroxide (5 mL) andstirred overnight. The mixture was diluted with ethyl acetate, washedwith 1 molar hydrochloric acid (×2), dried and evaporated. The residuewas crystallized from a small amount of acetic acid to give the titlecompound (960 mg, 37%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 13.06 (br. s.,1H), 10.09 (br. s., 1H), 4.54 (t, J=11.12 Hz, 1H), 4.10 (d, J=5.81 Hz,2H), 2.22 (qd, 1H), 2.06 (q, J=7.33 Hz, 2H), 1.78 (d, J=12.38 Hz, 2H),1.46-1.69 (m, 9H), 1.28 (q, J=13.05 Hz, 2H), 1.11 (q, J=12.88 Hz, 1H),0.77 (t, J=7.45 Hz, 3H)

Example 129

N-{[1,3-Bis(2,6-dichlorophenyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine

129a) N,N′-Bis(2,6-dichlorophenyl)urea. 2,6 dichloroaniline (3.47 g,21.4 mmoles) and carbonyldiimidazole (3.24 g, 20 mmoles) were heatedtogether in dimethylformamide (75 mL) for 4 hours. The mixture wascooled and partitioned between ethyl acetate and 1 molar hydrochloricacid, which produced a solid. The solid was collected washed with ethylacetate, hexane and dried to give the title compound (940 mg, 27%). 1HNMR (400 MHz, DMSO-d₆) δ ppm 8.44 (s, 2H), 7.52 (d, J=8.08 Hz, 4H),7.28-7.35 (m, 2H)

129b) 1,3-Bis(2,6-dichlorophenyl)-2,4,6(1H,3H,5H)-pyrimidinetrione. Amixture of N,N′-bis(2,6-dichlorophenyl)urea (850 mg, 2.43 mmoles) andmalonyl dichloride (240 uL, 2.47 mmoles) in chloroform (500 mL) washeated under reflux for 3 hours. Another aliquot of malonyl dichloride(240 uL, 2.47 mmoles) was added and heating continued for a further 2hours. The mixture was filtered, evaporated and purified by flashchromatography (dichloromethane to 2% methanol in dichloromethane) togive the title compound (200 mg, 20%). 1H NMR (400 MHz, DMSO-d₆) δ ppm7.66 (d, J=8.08 Hz, 4H), 7.53 (t, J=8.08 Hz, 2H), 4.93 (br. s, 2H)

129c)N-{[1,3-Bis(2,6-dichlorophenyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine.A mixture of1,3-bis(2,6-dichlorophenyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (200 mg,0.478 mmoles), diisopropylethylamine (210 uL, 0.96 mmoles) and ethylisocyanatoacetate (126 uL, 0.574 mmoles) in dichloromethane (50 mL) wasstirred overnight. Reaction was very slow, therefore additionaldiisopropylethylamine (1.0 mL, 3.4 mmoles) and ethyl isocyanatoacetate(500 uL, 2.6 mmoles) was added and the mixture was heated batchwise(3×20 mL) in a microwave reactor at 120° C. for 20 minutes. The combinedreaction mixtures was washed with 1 molar hydrochloric acid (×2) andevaporated. The residue was dissolved in ethanol (5 mL), treated with 6molar sodium hydroxide (5 mL) and stirred for 1 hour. The mixture wasdiluted with ethyl acetate, washed with 1 molar hydrochloric acid (×2),dried and evaporated. The residue was crystallized from a small amountof acetic acid to give the title compound (138 mg, 55%). 1H NMR (400MHz, DMSO-d₆) δ ppm 13.25 (br. s., 1H), 10.11 (t, J=5.68 Hz, 1H),7.67-7.76 (m, 4H), 7.59 (dd, J=8.84, 7.58 Hz, 2H), 4.18 (d, J=5.56 Hz,2H).

BIOLOGICAL BACKGROUND

The following references set out information about the target enzymes,HIF prolyl hydroxylases, and methods and materials for measuringinhibition of same by small molecules.

-   M. Hirsilä, P. Koivunen, V. Günzler, K. I. Kivirikko, and J.    Myllyharju “Characterization of the Human Prolyl 4-Hydroxylases That    Modify the Hypoxia-inducible Factor” J. Biol. Chem., 2003, 278,    30772-30780.-   C. Willam, L. G. Nicholls, P. J. Ratcliffe, C. W. Pugh, P. H.    Maxwell “The prolyl hydroxylase enzymes that act as oxygen sensors    regulating destruction of hypoxia-inducible factor α” Advan. Enzyme    Regul., 2004, 44, 75-92-   M. S. Wiesener, J. S. Jürgensen, C. Rosenberger, C. K.    Scholze, J. H. Hörstrup, C. Warnecke, S. Mandriota, I.    Bechmann, U. A. Frei, C. W. Pugh, P. J. Ratcliffe, S.    Bachmann, P. H. Maxwell, and K.-U. Eckardt “Widespread    hypoxia-inducible expression of HIF-2α in distinct cell populations    of different organs” FASEB J., 2003, 17, 271-273.-   S. J. Klaus, C. J. Molineaux, T. B. Neff, V. Guenzler-Pukall, I.    Lansetmo Parobok, T. W. Seeley, R. C. Stephenson “Use of    hypoxia-inducible factor α (HIFα) stabilizers for enhancing    erythropoiesis” PCT Int. Appl. (2004), WO 2004108121 A1-   C. Warnecke, Z. Zaborowska, J. Kurreck, V. A. Erdmann, U. Frei, M.    Wiesener, and K.-U. Eckardt “Differentiating the functional role of    hypoxia-inducible factor (HIF)-1α and HIF-2α (EPAS-1) by the use of    RNA interference: erythropoietin is a HIF-2a target gene in Hep3B    and Kelly cells” FASEB J., 2004, 18, 1462-1464.    For the Expression of EGLN3 See:-   R. K. Bruick and S. L. McKnight “A Conserved Family of    Prolyl-4-Hydroxylases That Modify HIF” Science, 2001, 294,    1337-1340.    For the Expression of HIF2α-CODD See:-   a) P. Jaakkola, D. R. Mole, Y.-M. Tian, M. I. Wilson, J.    Gielbert, S. J. Gaskell, A. von Kriegsheim, H. F. Hebestreit, M.    Mukherji, C. J. Schofield, P. H. Maxwell, C. W. Pugh, P, J.    Ratcliffe “Targeting of HIF-α to the von Hippel-Lindau    Ubiquitylation Complex by O₂-Regulated Prolyl Hydroxylation”    Science, 2001, 292, 468-472.-   b) M. Ivan, K. Kondo, H. Yang, W. Kim, J. Valiando, M. Ohh, A.    Salic, J. M. Asara, W. S. Lane, W. G. Kaelin Jr. “HIFα Targeted for    VHL-Mediated Destruction by Proline Hydroxylation: Implications for    O₂ Sensing” Science, 2001, 292, 464-468.    For the Expression of VHL, Elongin b and Elongin c See:-   A. Pause, S. Lee, R. A. Worrell, D. Y. T. Chen, W. H. Burgess, W. M.    Linehan, R. D. Klausner “The von Hippel-Lindau tumor-suppressor gene    product forms a stable complex with human CUL-2, a member of the    Cdc53 family of proteins” Proc. Natl. Acad. Sci. USA, 1997, 94,    2156-2161.    Biological Assay(s)    EGLN3 Assay    Materials:

His-MBP-EGLN3 (6HisMBPAttB1EGLN3(1-239)) was expressed in E. Coli andpurified from an amylase affinity column. Biotin-VBC[6HisSumoCysVHL(2-213), 6HisSumoElonginB(1-118), and6HisSumoElonginC(1-112)] and His-GB1-HIF2α-CODD(6HisGB1tevHIF2A(467-572)) were expressed from E. Coli.

Method:

Cy5-labelled HIF2a CODD, and a biotin-labeled VBC complex were used todetermine EGLN3 inhibition. EGLN3 hydroxylation of the Cy5CODD substrateresults in its recognition by the biotin-VBC. Addition of aEuropium/streptavidin (Eu/SA) chelate results in proximity of Eu to Cy5in the product, allowing for detection by energy transfer. A ratio ofCy5 to Eu emission (LANCE Ratio) is the ultimate readout, as thisnormalized parameter has significantly less variance than the Cy5emission alone.

Then 50 nL of inhibitors in DMSO (or DMSO controls) were stamped into a384-well low volume Corning NBS plate, followed by addition of 2.5 μL ofenzyme [50 mL buffer (50 mM HEPES/50 mM KCl)+1 mL of a 10 mg/mL BSA inbuffer+6.25 μL of a 10 mg/mL FeCl₂ solution in water+100 μL of a 200 mMsolution of ascorbic acid in water+15.63 μL EGLN3] or control [50 mLbuffer+1 mL of a 10 mg/mL BSA in buffer+6.25 μL of a 10 mg/mL FeCl₂solution in water+100 μL of a 200 mM solution of ascorbic acid inwater]. Following a 3 minutes incubation, 2.5 μL of substrate [50 mLBuffer+68.6 μL biotin-VBC+70.4 μL Eu (at 710 μg/mL stock)+91.6 μLCy5CODD+50 μL of a 20 mM solution of 2-oxoglutaric acid in water+0.3 mMCHAPS] was added and incubated for 30 minutes. The plate was loaded intoa PerkinElmer Viewlux for imaging. For dose response experiments,normalized data were fit by ABASE/XC50 using the equationy=a+(b−a)/(1+(10{circumflex over ( )}x/10{circumflex over( )}c){circumflex over ( )}d), where a is the minimum % activity, b isthe maximum % activity, c is the pIC₅₀, and d is the Hill slope.

All exemplified compounds herein (Examples 1 to 129) have demonstratedin vitro EGLN3 inhibitory activity in this assay and have IC₅₀'s in therange of 0.8 nanomolar to 20 micromolar. This range represents the dataaccumulated as of the time of filing this application. Later testing mayshow variations in IC₅₀ data due to variations in reagents, conditionsand variations in the method(s) used from those given herein above.Thus, these values are to be viewed as illustrative rather thanabsolute.

Measure Epo Protein Produced by Hep3B Cell Line Using ELISA Method.

Hep3B cells obtained from the American Type Culture Collection (ATCC)are seeded at 2×10{circumflex over ( )}4 cells/well in Dulbecco'sModified Eagle Medium (DMEM)+10% FBS in 96-well plates. Cells areincubated at 37 deg C./5% CO2/90% humidity (standard cell cultureincubation conditions). After overnight adherence, medium is removed andreplaced with DMEM without serum containing test compound or DMSOnegative control. Following 48 hours incubation, cell culture medium iscollected and assayed by ELISA to quantitate Epo protein.

Of the exemplified compounds tested to date all, except Examples 8, 9,31, 35, 39, 88, 91, 93, and 94, have demonstrated EC₅₀'s in the Hep3BELISA assay in the range of 0.4 micromolar to 100 micromolar using thereagents and under the conditions outlined herein above. Examples 8, 9,31, 35, 39, 88, 91, 93, and 94, have demonstrated EC₅₀'s in the Hep3BELISA assay of greater than 100 micromolar, the maximum concentrationtested. This range represents the data accumulated as of the time of thefiling of this application. Later testing may show variations in EC₅₀data due to variations in reagents, conditions and variations in themethod(s) used from those given herein above. Thus, these values are tobe viewed as illustrative rather than absolute.

These compound are believed to be useful in therapy as defined above andto not have unacceptable or untoward effects when used in compliancewith a permitted therapeutic regime.

The foregoing examples and assay have been set forth to illustrate theinvention, not limit it. What is reserved to the inventors is to bedetermined by reference to the claims.

What is claimed is:
 1. A compound according to formula (I):

wherein: R¹ and R⁴ are each independently selected from the groupconsisting of hydrogen, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl,C₃-C₈cycloalkyl, C₃-C₈cycloalkyl-C₁-C₁₀alkyl, C₅-C₈cycloalkenyl,C₅-C₈cycloalkenyl-C₁-C₁₀alkyl, C₃-C₈heterocycloalkyl,C₃-C₈heterocycloalkyl-C₁-C₁₀alkyl, aryl, aryl-C₁-C₁₀alkyl, heteroaryland heteroaryl-C₁-C₁₀alkyl; R² is —OR⁹; R³ is H; R⁹ is H or a cation; Xis O; and Y is O; where any carbon or heteroatom of R¹, and R⁴ isunsubstituted; and a pharmaceutically acceptable salt thereof.
 2. Amethod of treating anemia in a human in need thereof which comprisesadministering to such human a therapeutically effective amount of acompound as described in claim
 1. 3. A method of treating anemia in ahuman in need thereof which comprises administering to such human atherapeutically effective amount ofN-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine,or a pharmaceutically acceptable salt thereof.
 4. A method of treatinganemia in a human in need thereof which comprises administering to suchhuman a therapeutically effective amount ofN-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine.